Compositions and methods for the treatment of hypertension or oedemas

ABSTRACT

The invention relates to a series of new compounds, salts thereof and to methods for the preparation of the compounds which have the general formula ##STR1## in which R 1  stands for an unsubstituted or substituted phenoxy, phenylthio, benzyl, phenylsulfinyl, or anilino radical; 
     R 2  stands for a --YR 2  &#39; radical, in which Y represents --O--, --S--, or --NH--, and R 2  &#39; represents C 1  -C 6  -alkyl, C 2  -C 6  -alkenyl or -alkynyl; or methyl or ethyl substituted with phenyl, furyl, thienyl or pyridyl; 
     R 3  and R 4  which can be the same or different, and unsubstituted or substituted, stand for hydrogen or for a straight or branched C 1  -C 8  -alkyl, C 2  -C 8  -alkenyl or -alkynyl radical, a C 5  -C 7  -cycloalkyl, a phenyl, or a 5-, 6- or 7-membered heterocyclic ring system containing not more than two hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen, or for a C 1  -C 3  alkyl radical substituted with phenyl or with a 5-, 6- or 7-membered heterocyclic ring system containing not more than two hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen; and 
     R 4  furthermore stands for a lower carbalkoxy radical, a C 1  -C 6  alkanoyl radical, or a benzoyl radical; and 
     salts thereof with pharmaceutically acceptable acids. 
     The compounds of the invention possess a pronounced diuretic and/or saluretic activity with a very low excretion of potassium ions. The low toxicity also makes the present compounds particularly valuable in human and veterinary practice.

This is a division, of application Ser. No. 696,547 filed June 16, 1976,now U.S. Pat. No. 4,082,851 filed Apr. 4, 1978.

This invention relates to a series of new compounds, salts thereof andto methods for the preparation of the compounds which are valuable inthe human and veterinary practice and have the general formula ##STR2##in which

R₁ stands for an unsubstituted or substituted phenoxy, phenylthio,benzyl, phenylsulfinyl, or anilino radical;

R₂ stands for a --YR₂ ' radical, in which Y represents --O--, --S--, or--NH--, and R₂ ' represents C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl or -alkynyl;or methyl or ethyl substituted with phenyl, furyl, thienyl or pyridyl;

R₃ and R₄ which can be the same or different, and unsubstituted orsubstituted, stand for hydrogen or for a straight or branched C₁ -C₈-alkyl, C₂ -C₈ -alkenyl or -alkynyl radical, a C₅ -C₇ -cycloalkyl, aphenyl, or a 5-, 6- or 7-membered heterocyclic ring system containingnot more than two hetero atoms selected from the group consisting ofoxygen, sulphur and nitrogen, or for a C₁ -C₃ alkyl radical substitutedwith phenyl or with a 5-, 6- or 7-membered heterocyclic ring systemcontaining not more than two hetero atoms selected from the groupconsisting of oxygen, sulphur and nitrogen; and

R₄ furthermore stands for a lower carbalkoxy radical, a C₁ -C₆ alkanoylradical, or a benzoyl radical; and

salts thereof with pharmaceutically acceptable acids.

More specifically, R₂ ' when representing an alkenyl or alkynyl radical,stands for a radical with three to five carbon atoms.

More specifically, R₃ and R₄ may each represent hydrogen, C₁ -C₈ alkyl,C₃ -C₅ -alkenyl, C₅ -C₇ -cycloalkyl, phenyl, furyl, thienyl,morpholinyl, pyridyl, or R₃ and R₄ each represents C₁ -C₃ alkylsubstituted with one or two phenyl radicals or with furyl,tetrahydrofuryl, pyridyl and piperidyl, or R₄ represents carbethoxy, C₂-C₄ alkanoyl or benzoyl.

As examples of radicals falling within the above definitions and thedefinitions used in the present specification, mention may especially bemade of:

Alkyl: methyl, ethyl, different isomers of propyl, butyl, pentyl, hexyl,heptyl, octyl;

cycloalkyl: cyclopentyl, cyclohexyl and cycloheptyl;

alkenyl: different isomers of propenyl butenyl, pentenyl;

alkynyl: 1- and 2-propynyl;

heterocyclic radicals: furyl, thienyl, pyrrolidyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl,piperidyl, tetrahydropyridazinyl, hexahydropyridazinyl, pyrimidyl,pyrazinyl, morpholinyl, thiazinyl, perhydroazepinyl, hexahydrooxepinyl.

The above substituents R₁, R₂ ', R₃, and R₄ can be substituted indifferent positions with different groups, such as one or more halogenatoms, e.g. fluorine, chlorine or bromine atoms, lower alkyl, halo-loweralkyl, e.g. trifluoromethyl; nitro and amino groups, mono- ordialkylamino or acylamino groups, hydroxy groups, which may beetherified, e.g. lower alkoxy, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy or isobutoxy, or esterified with lower aliphaticcarboxylic acids, such as lower alkanoic acids, e.g. acetic, propionicor pivalic acid, lower alkenoic acids, e.g. acrylic or methacrylic acid,or with lower aliphatic dicarboxylic acids, e.g. oxalic, malonic,succinic, glutaric, adipic, maleic or fumaric acid or their acid esterswith lower alkanols, e.g. methanol or ethanol; or etherified mercaptogroups such as methylthio, ethylthio, isopropylthio, butylthio,isobutylthio or phenylthio radicals.

Whenever the expression "lower" is used in the foregoing and in thefollowing connection with an organic radical it indicates a content offrom 1 to 6 carbon atoms.

The salts of the compounds of the invention are pharmaceuticallyacceptable salts, and include, for example, salts with non-toxic,pharmaceutically acceptable acids, such as hydrochloric and hydrobromicacid, phosphoric acid, nitric acid, p-toluenesulfonic acid,methanesulfonic acid, formic acid, acetic acid, propionic acid, citricacid, tartaric acid and maleic acid.

Of particular value are the following combinations of substituents:

(a) Compounds of formula I in which R₁ stands for an unsubstituted orsubstituted phenoxy or phenylthio radical and Y stands for --NH--.

(b) Compounds of formula I in which R₁ stands for an unsubstituted orsubstituted phenoxy or phenylthio radical and Y stands for --S--.

(c) Compounds of formula I in which R₁ stands for an unsubstituted orsubstituted anilino radical and Y stands for --NH--.

(d) Compounds of formula I in which R₁ stands for an unsubstituted orsubstituted benzyl radical and Y stands for --NH--.

(e) Compounds of formula I in which R₁ stands for an unsubstituted orsubstituted benzyl radical and Y stands for --O-- or --S--.

It has been found that the compounds of the invention possess apronounced diuretic and/or saluretic activity with a very low excretionof potassium ions. The low toxicity also makes the present compoundsparticularly valuable in human and veterinary practice.

Furthermore the compounds of the invention are capable of producing agreat maximal natriuretic effect exceeding the thiazides and thiazidetype diuretics in this respect. This is especially of importance in thetreatment of patients with severe renal failure and/or severe cardiacinsufficiency. The rational drugs used for this indication areethacrynic acid, furosemide and bumetanide. These drugs are organicacids and therefore excreted by the organic acid secretory mechanism.The compounds of the invention are distinguished from these drugs by notbeing carboxylic acids and therefore do not compete neither with otheracidic drugs like penicillin nor with naturally occurring acidicmetabolites. This is of importance with respect to drug interaction dueto a limited capacity of the acid secretory transport.

Japanese patent applications Nos. 45228/62 and 27746/63 describe amethod for the preparation of chlorosulfamylbenzylamines, thesecompounds having value as intermediates, and, according to the Japanesespecifications, possessing some diuretic effect when administered inrats. However, in experiments performed in connection with the presentinvention, it was impossible to verify a useful diuretic effect whenadministering in doses of the same magnitude as used for the presentcompounds.

The present compounds are effective after oral, enteral or parenteraladministration, and are preferably prescribed in the form of tablets,pills, dragees, or capsules containing a compound of formula I or a saltthereof as defined above, mixed with carriers and/or auxiliary agents.

Salts, which are soluble in water, can advantageously be administered byinjection as aqueous solutions. The compounds of the invention areuseful in the treatment of oedematous conditions, e.g. cardiac, hepatic,renal, and pulmonary oedema, and of pathological conditions whichproduce an abnormal retension of the electrolytes of the body, and inthe treatment of hypertension.

In pharmaceutical compositions containing the compounds of theinvention, organic or inorganic, solid or liquid carriers suitable fororal, enteral, or parenteral administration can be used to make up thecomposition. Gelatine, lactose, starch, magnesium stearate, talc,vegetable and animal fats and oils, gum, polyalkylene glycol, or otherknown carriers for medicaments are all suitable as carriers.

The pharmaceutical compositions can be prepared as slow-releaseformulations. It should, however, be noted that certain compounds offormula I in themselves show an advantageous prolonged diuretic effect.

In the pharmaceutical compositions, the proportion of therapeuticallyactive material to carrier substances can vary between 0.5 percent and90 percent.

The compositions may further contain other therapeutic compounds appliedin the treatment of, for example oedemas and hypertension, besides thewellknown auxiliary agents. Such other compounds can be, for instanceβ-adrenergic receptor blocking drugs e.g. propranolol or timolol, orother synthetic hypotensive compounds, e.g. hydralazine, or otherdiuretics and saluretics, such as the well-known benzothiadiazines andthiazide type diuretics, e.g. hydroflumethiazide and chlorthalidone;potassium-sparing diuretics, e.g. triamterene can also be used in thepreparation of the compositions. It can also be desirable to add smallamounts of aldosterone antagonists, e.g. spironolactone, or to combinethe compounds of the invention with a slow-release formulation of apotassium salt. It has also been found that by combination of a compoundwith the general formula I with some of the therapeutic compounds asdescribed above the activity of both compounds can be enhanced. In thatmanner a higher therapeutic effect is achieved with the combination thanwith either of the two compounds alone.

It is another object of the invention to provide a method of preparingthe compounds of the invention.

The compounds of formula I can be prepared by different methods. In onemethod, a compound of the formula II ##STR3## in which R₁ and R₂ havethe meanings defined before, and X is capable of forming a "good leavinggroup", X thus standing for e.g. a halogen atom such as chlorine,bromine or iodine, an alkyl- or arylsulphonyloxy group, achlorosulphonyloxy group, an alkylsulphate group, a hydrogensulphategroup, an alkylsulphite group, a mono- or dialkylphosphate group, analkylchlorophosphate group or a nitrate group, is reacted with an amine##STR4## in which R₃ and R₄ have the meanings defined before, to formthe desired compound of formula I.

The starting material of formula II can be prepared according to thefollowing reaction scheme: ##STR5## in which formulae R₁ has the abovemeanings, --COOR₅ indicates a carboxylic ester group, R₅ being, forinstance, lower alkyl, and R₈ stands for R₂ or --YH. In case R₈ standsfor --YH, the obtained compound of formula III is thereafter alkylatedto form a compound of formula III, in which R₈ stands for R₂.

The compounds of formula IV are known (for instance from the BritishPat. Nos. 1,249,490, and 1,327,481, and British Pat. applications Nos.19959/72, 32909/72, 51384/72, 53043/72, 3658/73 and 42050/73) or can beprepared by conventional methods for preparing analogous knowncompounds.

The step of converting a compound of formula IV to a compound of formulaIII is carried out by a reduction process, e.g. by using lithiumaluminium hydride, but other agents and processes can be used as well.The benzyl alcohol derivative of formula III is thereafter convertedinto a compound of formula II by conventional methods for thepreparation of esters of mineralic and sulphonic acids with alcohols,well known to the man skilled in the art.

In another method, a compound of the formula V ##STR6## in which R₁ andR₂ have the above meanings, is converted into a compound of formula I bya reductive alkylation, e.g. by reaction with an amine H₂ NR₃, in whichR₃ has the above meanings, followed by a hydrogenation in the presenceof a suitable catalyst, or by reduction, e.g. with alkali metalborohydrides. The hydrogenation can also be carried out simultaneouslywith the reaction with the amine H₂ NR₃.

The starting material of formula V can for instance be prepared byoxidizing a compound of formula III, for instance with chromic anhydridein pyridine, or with another suitable oxidating agent. The compounds ofof formula V can also be prepared from a compound of formula IV oranother suitable acid derivative, e.g. an acid halide or anhydridecorresponding to formula VI IV by subjecting such compounds to areduction under milder conditions than those described above inconnection with the first method.

In still another method, a compound of the formula VI ##STR7## in whichR₁, R₂, R₃, and R₄ have the above meanings, is subjected to a reductionprocess, for instance with lithium aluminium hydride, to form thedesired compound of formula I.

The compounds of formula VI can be prepared from the free acidscorresponding to the compound of formula IV, the free acids beingconverted into a reactive derivative thereof, such as an acid halide, oran anhydride, the reactive derivative thus obtained being reacted withan amine HNR₃ R₄, R₃ and R₄ having the above meanings.

In a further method, a compound of the formula VII ##STR8## in which R₁and R₂ have the above meanings, is subjected to a reduction process,forming a compound of formula I, in which R₃ and R₄ stand for hydrogen.

The compounds of formula VII can be prepared from the compounds offormula V by reaction with hydroxylamine.

Still a further method for producing a compound of formula I, in whichR₃ and R₄ stand for hydrogen, consists in subjecting a compound offormula VIII ##STR9## in which R₁ and R₂ have the meanings definedabove, to a reduction process.

The starting material of formula VIII can be prepared from compounds offormula VI (R₃ =R₄ =H) by dehydration.

Compounds of formula I can further be prepared by other methods, e.g. asillustrated by one of the following reaction schemes: ##STR10##

The intermediates of formulae III, V and VII are new compounds, whichcan also be used for the production of other final compounds than theones covered by formula I. Therefore the compounds of formulae III, Vand VII also form part of the present invention.

It should be mentioned, too, that the compounds of formula III and Vshow a pronounced diuretic and saluretic activity. The compounds offormula VII are especially valuable in causing an increased urinaryexcretion of water and sodium chloride while the excretion of potassiumis not influenced.

Another object of the invention resides in the selection of a dose ofthe compounds of the invention which dose can be administered so thatthe desired activity is achieved without simultaneous secondary effects.In the human therapy, the compounds and their salts are convenientlyadministered (to adults) in dosage units containing not less than 0,1 mgand up to 50 mg, preferably from 0.25 to 25 mg, calculated as thecompound of formula I.

By the term "dosage unit" is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically stable unit dosecomprising either the active material as such or a mixture of it withsolid or liquid pharmaceutical diluents or carriers.

In the form of a dosage unit, the compound may be administered once ormore times a day at appropriate intervals, always depending, however, onthe condition of the patient, and in accordance with the prescriptionmade by the medical practitioner.

Thus an appropriate daily dose would be an amount of from 0,25 to 100 mgof a compound of formula I.

If the composition is to be injected, a sealed ampoule, a vial or asimilar container may be provided containing a parenterally acceptableaqueous or oily injectable solution or dispersion of the active materialas the dosage unit.

The parenteral preparations are in particular useful in the treatment ofconditions in which a quick response to the treatment is desirable. Inthe continuous therapy the tablets or capsules may be the appropriateform of pharmaceutical preparation, e.g. owing to the prolonged effectobtained when the drug is given orally. If desired, the compounds may beadministered in the form of sustained-release formulations.

In the treatment of various diseases, such tablets may advantageouslycontain other active agents as mentioned hereinbefore.

Still another object of the invention is to provide a method of treatingpatients suffering from oedematous conditions, e.g. cardiac, hepatic,renal, and pulmonary oedema, and from pathological conditions whichcause an abnormal retention of the electrolytes in the body, and/or fromhypertension, the method comprising administering to adult patients from0.25 to 100 mg per day of a compound of formula I or an equivalentamount of a salt as defined above, optionally together with other activeagents as described above.

It is to be understood that it is not necessary to administrate both theactive components of the formula I and other therapeutic agents, asdescribed above by using a composition according to the invention whichcontains both these components. The most important thing is that boththe active components are administered in such a way that they are ableto act synergistically within the body. As a rule this means that bothcomponents must be administered simultaneously, i.e. at such an intervalthat it is possible for the compounds to act synergistically.

Preferably, the compound is given in the form of the dosage unitsaforesaid.

The invention will be further described in the following Examples whichare not to be construed as limiting the invention.

EXAMPLE 1. 4-Benzyl-3-methylthio-5-sulfamylbenzyl alcohol.

To a stirred mixture of lithium aluminium hydride (24 g) and dry diethylether (500 ml), a solution of ethyl4-benzyl-3-methylthio-5-sulfamylbenzoate (85 g) in dry diethyl ether (3liters) is dropwise added during 1-1.5 hours. After additional stirringfor 3 hours, the mixture is cooled, and ethyl acetate (60 ml) followedby water (100 ml) and 4 N hydrochloric acid (1 liter) are verycautiously added dropwise. The organic layer is separated, washed with 4N hydrochloric acid and with water, and dried in the presence ofmagnesium sulphate. After filtration, the solvents are removed in vacuoto yield crude 4-benzyl-3-methylthio-5-sulfamylbenzyl alcohol. Afterrecrystallization from ethanol it is obtained with a melting point of190°-192° C.

EXAMPLE 2. 3-Amino-4-phenoxy-5-sulfamylbenzyl alcohol.

To a stirred mixture of lithium aluminium hydride (12.5 g) and drydioxane (250 ml), a solution of ethyl3-amino-4-phenoxy-5-sulfamylbenzoate (50 g) in dry dioxane (250 ml) isdropwise added at 90° C. during about one hour. After additionalstirring and heating for 3 hours, the mixture is cooled, and ethylacetate (25 ml) followed by water (50 ml) and 4 N acetic acid (310 ml)are very cautiously added dropwise. The solvents are thereafter removedin vacuo, and the residue is extracted with ethyl acetate (1 liter). Theinsoluble inorganic material is removed by filtration, and the filtrateis washed with aqueous sodium hydrogen carbonate and with water, and isthen dried in the presence of magnesium sulphate. After filtration, thesolvent is removed in vacuo to yield crude3-amino-4-phenoxy-5-sulfamylbenzyl alcohol. After recrystallization fromaqueous ethanol it is obtained with a melting point of 170° C.

EXAMPLE 3. 3-Amino-4-(3'-trifluoromethylphenoxy)-5-sulfamylbenzylalcohol.

To a stirred mixture of lithium aluminium hydride (5.0 g) and dry1,2-dimethoxyethane (100 ml), a solution of ethyl3-amino-4-(3'-trifluoromethylphenoxy)-5-sulfamylbenzoate (20 g) in dry1,2-dimethoxyethane (100 ml) is dropwise added at 100° C. during about 1hour. After additional stirring and heating for 3 hours, the mixture iscooled, and ethyl acetate (10 ml) followed by water (20 ml) and 4 Nacetic acid (125 ml) are very cautiously added dropwise. The solventsare thereafter removed in vacuo and the residue is extracted with ethylacetate (300 ml). The insoluble inorganic material is removed byfiltration, and the filtrate is washed with aqueous sodium hydrogencarbonate and with water, and is then dried in the presence of magnesiumsulphate. After filtration, the solvent is removed in vacuo to yieldcrude 3-amino-4-(3'trifluoromethylphenoxy)-5-sulfamylbenzyl alcohol.After recrystallization from diethyl ether/petroleum ether it isobtained with a melting point of 133°-134° C.

EXAMPLE 4. 3-Amino-4-benzyl-5-sulfamylbenzyl alcohol.

To a stirred mixture of lithium aluminium hydride (12 g) and dry diethylether (350 ml), a solution of methyl 3-amino-4-benzyl-5-sulfamylbenzoate(30 g) in dry pyridine (300 ml) is dropwise added during 1-1.5 hours.After additional stirring for 3 hours, the mixture is cooled and ethylacetate (25 ml) followed by water (50 ml) are very cautiously addeddropwise. After stirring for a further 30 minutes, the solids arecollected by filtration and dried in air. The filter cake is treatedwith hot 4 N hydrochloric acid (about 500 ml) to dissolve inorganicmaterial. After cooling 3-amino-4-benzyl-5-sulfamylbenzyl alcohol iscollected by filtration and dried in air. After recrystallization fromaqueous ethanol it is obtained with a melting point of 159°-161° C.

EXAMPLE 5. 3-Methylamino-4-phenoxy-5-sulfamylbenzyl alcohol.

A mixture of 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol (8.8 g; preparedas described in Example 2), methyl iodide (2.1 ml), sodium hydrogencarbonate (5.0 g) and hexamethylphosphoric triamide (45 ml) is stirredat 22°-25° C. for 18 hours. The mixture is then diluted with water(about 500 ml) to precipitate crude3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol. Afterrecrystallization from aqueous ethanol it is obtained with a meltingpoint of 167°-168° C.

EXAMPLE 6. 3-(2'-Furfurylamino)-4-phenoxy-5-sulfamylbenzyl alcohol.

A solution of 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol (14.7 g;prepared as described in Example 2) and furfural (6 ml) in methanol (150ml) is refluxed for 18 hours. Sodium borohydride (4.0 g) is thereafterduring about one hour added in portions to the stirred solution, keepingthe temperature at 0°-5° C. by external cooling. After additionalstirring for 2 hours, 2 N acetic acid (100 ml) is cautiously addeddropwise, whereafter the methanol is removed in vacuo. The residue isdiluted with water to precipitate crude3-(2'-furfurylamino)-4-phenoxy-5-sulfamylbenzyl alcohol. Afterrecrystallization from ethanol it is obtained with a melting point of162°-163° C.

EXAMPLES 7-50

By following, as defined in Table I below, the procedures described inExamples 1-6, but using as starting materials an equimolar amount of theappropriate alkyl 4-R₁ -3-R₂ -5-sulfamylbenzoate or the appropriate 4-R₁-3-NH₂ -5-sulfamylbenzyl alcohol, and, when following the procedures ofExamples 5 or 6, the appropriate alkyl halogenide or aldehyde,respectively, the 4-R₁ -3-R₂ -5-sulfamylbenzyl alcohols of Table I areobtained.

                                      Table I.                                    __________________________________________________________________________         Example(s) in which                                                           the procedure(s) used                                                    Ex. No                                                                             is (are) described                                                                        Reaction product    Mp °C.                            __________________________________________________________________________     7   5           3-ethylamino-4-phenoxy-5-                                                     sulfamylbenzyl alcohol                                                                            165-167                                   8   5           3-allylamino-4- phenoxy-5-                                                    sulfamylbenzyl alcohol                                                                            141-142                                   9   4 and 5     4-phenoxy-3-propargylamino-                                                   5-sulfamylbenzyl alcohol                                                                          164-166                                  10   4 and 5     3-n-butylamino-4-phenoxy-5-                                                   sulfamylbenzyl alcohol                                                                            157-158                                  11   5           3-crotylamino-4-phenoxy-5-                                                    sulfamylbenzyl alcohol                                                                            171-173                                  12   5           3-n-pentylamino-4-phenoxy-                                                    5-sulfamylbenzyl alcohol                                                                          142-144                                  13   5           3-isopentylamino-4-phenoxy-                                                   5-sulfamylbenzyl alcohol                                                                          121-123                                  14   4 and 5     3-benzylamino-4-phenoxy-5-                                                    sulfamylbenzyl alcohol                                                                            205-206                                  15   6           4-phenoxy-3-(2'-thenylamino)-                                                 5-sulfamylbenzyl alcohol                                                                          194-196                                  16   6           4-phenoxy-3-(2'-pyridylmethyl-                                                amino)-5-sulfamylbenzyl alcohol                                                                   169-170                                  17   6           4-phenoxy-3-(3'-pyridylmethyl-                                                amino)-5-sulfamylbenzyl alcohol                                                                   198-200                                  18   2           3-amino-4-(4'-methoxyphenoxy)-                                                5-sulfamylbenzyl alcohol                                                                          172-173                                  19   5           3-n-butylamino-4-(4'-methoxyphen-                                             oxy)-5-sulfamylbenzyl alcohol                                                                     129-131                                  20   5           3-benzylamino-4-(4'-methoxyphenoxy)-                                          5-sulfamylbenzyl alcohol                                                                          200-202                                  21   5           3-benzylamino-4-(3'-trifluoromethyl-                                          phenoxy)-5-sulfamylbenzyl alcohol                                                                 153-155                                  22   2           3-amino-4-phenylthio-5-sulfamyl-                                              benzyl alcohol      168                                      23   5           3-n-butylamino-4-phenylthio-5-                                                sulfamylbenzyl alcohol                                                                            103-105                                  24   5           3-benzylamino-4-phenylthio-5-                                                 sulfamylbenzyl alcohol                                                                            172-174                                  25   2           3-amino-4-(2'-methylphenylthio)-                                              5-sulfamylbenzyl alcohol                                                                          170-171                                  26   5           3-n-butylamino-4-(2'-methylphenyl-                                            thio)-5-sulfamylbenzyl alcohol                                                                     86-88                                   27   5           3-benzylamino-4-(2'-methylphenyl)                                             thio)-5-sulfamylbenzyl alcohol                                                                    170-172                                  28   2           3-amino-4-anilino-5-sulfamyl-                                                 benzyl alcohol      144-145                                  29   5           4-anilino-3-n-butylamino-5-sulfamyl-                                          benzyl alcohol      144-145                                  30   5           4-anilino-3-benzylamino-5-sulfamyl-                                           benzyl alcohol      135-137                                  31   2           3-amino-4-(4'-chloroanilino)-5-                                               sulfamylbenzyl alcohol                                                                            137-139                                  32   5           3-n-butylamino-4-(4'-chloroanilino)-                                          5-sulfamylbenzyl alcohol                                                                          129-131                                  33   5           3-benzylamino-4-(4'-chloroanilino)-                                           5-sulfamylbenzyl alcohol                                                                          145-147                                  34   1 and 5     4-benzyl-3-ethylamino-5-sulfamyl-                                             benzyl alcohol      163-165                                  35   4 and 5     4-benzyl-3-n-butylamino-5-sulfamyl-                                           benzyl alcohol      145-147                                  36   4 and 5     4-benzyl-3-benzylamino-5-sulfamyl-                                            benzyl alcohol      179-180                                  37   6           4-benzyl-3-(2'-furfurylamino)-5-                                              sulfamylbenzyl alcohol                                                                            166-168                                  38   4           4-benzyl-3-methoxy-5-sulfamyl-                                                benzyl alcohol      186-188                                  39   4           4-benzyl-3-ethoxy-5-sulfamyl-                                                 benzyl alcohol      115-117                                  40   4           4-benzyl-3-n-propoxy-5-sulfamyl-                                              benzyl alcohol      118-119                                  41   1           4-benzyl-3-isopropoxy-5-sulfamyl-                                             benzyl alcohol      152-153                                  42   4           4-benzyl-3-n-butoxy-5-sulfamyl-                                               benzyl alcohol      111-115                                  43   4           4-benzyl-3-isopentyloxy-5-sulfamyl-                                           benzyl alcohol       92-95                                   44   4           4-benzyl-3-benzyloxy-5-sulfamyl-                                              benzyl alcohol      142-144                                  45   1           4-benzyl-3-ethylthio-5-sulfamyl-                                              benzyl alcohol      117-118                                  46   1           3-allylthio-4-benzyl-5-sulfamyl-                                              benzyl alcohol      93-94                                    47   1           4-benzyl-3-n-butylthio-5-sulfamyl-                                            benzyl alcohol      109-111                                  48   1           4-benzyl-3-benzylthio-5-sulfamyl-                                             benzyl alcohol      113-114                                  49   1           4-benzyl-3-(2'-phenethylthio)-5-                                              sulfamylbenzyl alcohol                                                                            124-125                                  50   2           4-benzyl-3-(2'-pyridylmethylthio)-                                            5-sulfamylbenzyl alcohol                                                                          129-131                                  __________________________________________________________________________

EXAMPLE 51. 4-Phenoxy-3-(4'-pyridylethyl-(2)-amino)-5-sulfamylbenzylalcohol.

A solution of 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol (14.7 g;prepared as described in Example 2), 4-vinylpyridine (10 ml) and aceticacid (10 ml) in 2-methoxyethanol (75 ml) is heated on a steam-bath for24 hours. The solution is then diluted with water (75 ml) to precipitatecrude 4-phenoxy-3-(4'-pyridylethyl-(2)-amino)-5-sulfamylbenzyl alcohol.After recrystallization from ethanol it is obtained with a melting pointof 188°-189° C.

EXAMPLE 52. 3-Benzylamino-4-phenylsulfinyl-5-sulfamylbenzyl alcohol.

A mixture of 3-benzylamino-4-phenylthio-5-sulfamylbenzyl alcohol (8.0 g;prepared as described in Example 24), hydrogen peroxide (10 ml, 30% inwater) and acetic acid (80 ml) is stirred at 22°-25° C. for 24 hours.The resulting solution is diluted with water (40 ml) and cooled toprecipitate crude 3-benzylamino-4-phenylsulfinyl-5-sulfamylbenzylalcohol. After recrystallization from a mixture of ethanol and2-methoxyethanol it is obtained with a melting point of 213°-214° C.

EXAMPLE 53. 4-Benzyl-3-methylthio-5-sulfamylbenzyl bromide.

4-Benzyl-3-methylthio-5-sulfamylbenzyl alcohol (10 g; prepared asdescribed in Example 1) is while stirring added in portions to aceticacid saturated with dry hydrogen bromide (50 ml), and the mixture isstirred for 24 hours. The resulting solution is diluted with water (100ml) and cooled to precipitate crude4-benzyl-3-methylthio-5-sulfamylbenzyl bromide. After recrystallizationfrom methanol it is obtained with a melting point of 149°-150° C.

EXAMPLES 54-60.

By following the procedure described in Example 53 but replacing4-benzyl-3-methylthio-5-sulfamylbenzyl alcohol with other 4-R₁ -3-R₂-5-sulfamylbenzyl alcohols as defined in Table II below, thecorresponding 4-R₁ -3-R₂ -5-sulfamylbenzyl bromides of Table II areobtained.

                  Table II.                                                       ______________________________________                                              Example                                                                       in which                                                                      the                                                                           starting                                                                      material                                                                      is                                                                      Ex. No.                                                                             described                                                                              Reaction product    Mp °C.                              ______________________________________                                        54    42       4-benzyl-3-n-butoxy-5-sulfamyl-                                                                   129-130                                                   benzyl bromide                                                 55    45       4-benzyl-3-ethylthio-5-sulfamyl-                                              benzyl bromide      129-131                                    56    46       3-allylthio-4-benzyl-5-sulfamyl-                                              benzyl bromide      see below                                  57    47       4-benzyl-3-n-butylthio-5-                                                     sulfamylbenzyl bromide                                                                            see below                                  58    48       4-benzyl-3-benzylthio-5-                                                      sulfamylbenzyl bromide                                                                            see below                                  59    49       4-benzyl-3-(2'-phenethylthio)-                                                5-sulfamylbenzyl bromide                                                                          see below                                  60    50       4-benzyl-3-(2'-pyridylmethyl-                                                 thio)-5-sulfamylbenzyl bromide                                                                    see below                                  ______________________________________                                    

The benzylbromides of Examples 56-60 are obtained as oils or hygroscopicamorphous materials which are used as such in the next step withoutpurification.

EXAMPLE 61. 3-Amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide.

3-Amino-4-benzyl-5-sulfamylbenzyl alcohol (12.5 g; prepared as describedin Example 4) is while stirring added in portions to acetic acidsaturated with dry hydrogen bromide (60 ml), and the mixture is stirredfor 24 hours. The resulting solution is diluted with diethyl ether (150ml) and cooled to precipitate 3-amino-4-benzyl-5-sulfamylbenzyl bromidehydrobromide as a hygroscopic material with a melting point of 195°-198°C.

EXAMPLES 62-88.

By following the procedure described in Example 61 but replacing3-amino-4-benzyl-5-sulfamylbenzyl alcohol with other 4-R₁ -3-R₂-5-sulfamylbenzyl alcohols as defined in Table III below, thecorresponding 4-R₁ -3-R₂ -5-sulfamylbenzyl bromide hydrobromides ofTable III are obtained.

                                      Table III                                   __________________________________________________________________________         Ex. in which                                                                  the starting                                                                  material is                                                              Ex. No.                                                                            described                                                                            Reaction product    Mp °C.                                 __________________________________________________________________________    62    2     3-amino-4-phenoxy-5-sulfamylbenzyl                                            bromide hydrobromide                                                                              202-206                                       63    5     3-methylamino-4-phenoxy-5-sulfamyl-                                           benzyl bromide hydrobromide                                                                       185-187                                       64    7     3-ethylamino-4-phenoxy-5-sulfamyl-                                            benzyl bromide hydrobromide                                                                       136-138                                       65    8     3-allylamino-4-phenoxy-5-sulfamyl-                                            benzyl bromide hydrobromide                                                                       146-149                                       66    9     4-phenoxy-3-propargylamino-5-sulfamyl-                                        benzyl bromide hydrobromide                                                                       146-148                                       67   10     3-n-butylamino-4-phenoxy-5-sulfamyl-                                          benzyl bromide hydrobromide                                                                       178-181                                       68   12     3-n-pentylamino-4-phenoxy-5-sulfamyl-                                         benzyl bromide hydrobromide                                                                       177-180                                       69   13     3-isopentylamino-4-phenoxy-5-sulfamyl-                                        benzyl bromide hydrobromide                                                                       see below                                     70   14     3-benzylamino-4-phenoxy-5-sulfamyl-                                           benzyl bromide hydrobromide                                                                       146-147                                       71   16     4-phenoxy-3-(2'-pyridylmethylamino)-5-                                        sulfamylbenzyl bromide dihydrobromide                                                             see below                                     72   17     4-phenoxy-3-(3'-pyridylmethylamino)-5-                                        sulfamylbenzyl bromide dihydrobromide                                                             see below                                     73   19     3-n-butylamino-4-(4'-methoxyphenoxy)-                                         5-sulfamylbenzyl bromide hydrobromide                                                             178-180                                       74   20     3-benzylamino-4-(4'-methoxyphenoxy)-                                          5-sulfamylbenzyl bromide hydrobromide                                                             220-225                                       75   21     3-benzylamino-4-(3'-trifluoromethyl-                                          phenoxy)-5-sulfamylbenzyl bromide                                             hydrobromide        see below                                     76   23     3-n-butylamino-4-phenylthio-5-sulfamyl-                                       benzyl bromide hydrobromide                                                                       see below                                     77   24     3-benzylamino-4-phenylthio-5-sulfamyl-                                        benzyl bromide hydrobromide                                                                       139-141                                       78   26     3-n-butylamino-4-(2'-methylphenylthio)-                                       5-sulfamylbenzyl bromide hydrobromide                                                             see below                                     79   27     3-benzylamino-4-(2'-methylphenylthio)-                                        5-sulfamylbenzyl bromide hydrobromide                                                             144-145                                       80   29     4-anilino-3-n-butylamino-5-sulfamyl-                                          benzyl bromide hydrobromide                                                                       195-200                                       81   30     4-anilino-3-benzylamino-5-sulfamyl-                                           benzyl bromide hydrobromide                                                                       108-111                                       82   32     3-n-butylamino-4-(4'-chloroanilino)-                                          5-sulfamylbenzyl bromide hydrobromide                                                             215-218                                       83   33     3-benzylamino-4-(4'-chloroanilino)-5-                                         sulfamylbenzyl bromide hydrobromide                                                               see below                                     84   34     4-benzyl-3-ethylamino-5-sulfamyl-                                             benzyl bromide hydrobromide                                                                       see below                                     85   35     4-benzyl-3-n-butylamino-5-sulfamyl-                                           benzyl bromide hydrobromide                                                                       213-215                                       86   36     4-benzyl-3-benzylamino-5-sulfamyl-                                            benzyl bromide hydrobromide                                                                       176-177                                       87   51     4-phenoxy-3-(4'-pyridylethyl-(2)-                                             amino)-5-sulfamylbenzyl bromide                                               dihydrobromide      203-205                                       88   52     3-benzylamino-4-phenylsulfinyl-5-                                             sulfamylbenzyl bromide hydrobromide                                                               see below                                     __________________________________________________________________________

The benzylbromide hydrobromides of Examples 69, 71, 72, 75, 76, 78, 83,84 and 88 are obtained as hygroscopic solids or semisolids, which areused as such in the next step without purification.

EXAMPLE 89. 3-Methylamino-4-phenoxy-5-sulfamylbenzaldehyde.

To a stirred mixture of dry pyridine (15 ml) and dry methylene chloride(225 ml), chromic anhydride (9.0 g) is added in one portion, and themixture is stirred for 15 minutes. A solution of3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol (4.6 g; prepared asdescribed in Example 5) in acetone (25 ml) is then added in one portionand the mixture is stirred for a further 15 minutes. The resultinginorganic precipitate is removed by filtration and the filtrate isevaporated in vacuo. The residue is extracted with diethyl ether (300ml) and filtered to remove a small amount of insoluble material. Thediethyl ether is removed in vacuo to yield crude3-methylamino-4-phenoxy-5-sulfamylbenzaldehyde. After recrystallizationfrom ethanol it is obtained with a melting point of 166°-167° C.

EXAMPLES 90-109.

By following the procedure described in Example 89 but replacing3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol with equimolar amountsof other 4-R₁ -3-R₂ -5-sulfamylbenzyl alcohols as defined in Table IVbelow, the corresponding 4-R₁ -3-R₂ -5-sulfamylbenzaldehydes of Table IVare obtained.

                                      Table IV                                    __________________________________________________________________________         Ex. in which                                                                  the starting                                                                  material is                                                              Ex. No.                                                                            described                                                                            Reaction product   Mp °C.                                  __________________________________________________________________________    90    7     3-ethylamino-4-phenoxy-5-sulfamyl-                                            benzaldehyde       165-166                                        91    8     3-allylamino-4-phenoxy-5-sulfamyl-                                            benzaldehyde       109-111                                        92    9     4-phenoxy-3-propargylamino-5-                                                 sulfamylbenzaldehyde                                                                             105-108                                        93   10     3-n-butylamino-4-phenoxy-5-sulfamyl-                                          benzaldehyde       152-153                                        94   11     3-crotylamino-4-phenoxy-5-sulfamyl-                                           benzaldehyde       176-178                                        95   12     3-n-pentylamino-4-phenoxy-5-sulfamyl-                                         benzaldehyde       147-149                                        96    6     3-(2'-furfurylamino)-4-phenoxy-5-                                             sulfamylbenzaldehyde                                                                             154-156                                        97   15     4-phenoxy-5-sulfamyl-3-(2'-thenyl-                                            amine)benzaldehyde 164-166                                        98   51     4-phenoxy-3-(4'-pyridylethyl-(2)-                                             amino)-5-sulfamylbenzaldehyde                                                                    175-177                                        99   19     3-n-butylamino-4-(4'-methoxyphenoxy)-                                         5-sulfamylbenzaldehyde                                                                           133-135                                        100  20     3-benzylamino-4-(4'-methoxyphenoxy)-                                          5-sulfamylbenzaldehyde                                                                           191-193                                        101  35     4-benzyl-3-n-butylamino-5-sulfamyl-                                           benzaldehyde       127-129                                        102  37     4-benzyl-3-(2'-furfurylamino)-5-                                              sulfamylbenzaldehyde                                                                             147-149                                        103  38     4-benzyl-3-methoxy-5-sulfamyl-                                                benzaldehyde       139-141                                        104  39     4-benzyl-3-ethoxy-5-sulfamyl-                                                 benzaldehyde       137-138                                        105  40     4-benzyl-3-n-propoxy-5-sulfamyl-                                              benzaldehyde       133-134                                        106  41     4-benzyl-3-isopropoxy-5-sulfamyl-                                             benzaldehyde       128-130                                        107  42     4-benzyl-3-n-butoxy-5-sulfamyl-                                               benzaldehyde       136-137                                        108  43     4-benzyl-3-isopentyloxy-5-sulfamyl-                                           benzaldehyde       115-117                                        109  44     4-benzyl-3-benzyloxy-5-sulfamyl-                                              benzaldehyde       173-174                                        __________________________________________________________________________

EXAMPLE 110. (3-Amino-4-benzyl-5-sulfamylbenzyl)-n-butylamine.

A mixture of 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide (1.1g; prepared as described in Example 61), n-butylamine (5.0 ml) andmethanol (10 ml) is stirred at 22°-25° C. for 24 hours. The resultingsolution is then diluted with water (20 ml) to precipitate crude(3-amino-4-benzyl-5-sulfamylbenzyl)-n-butylamine. After filtration andrecrystallization from aqueous ethanol it is obtained with a meltingpoint of 141°-143° C.

EXAMPLES 111-190.

By following the procedure described in Example 110 but using asstarting materials the appropriate 4-R₁ -3-R₂ -5-sulfamylbenzyl bromide(or its hydrobromide) and amine as defined in Table V below, thecorresponding 4-R₁ -3-R₂ -5-sulfamyl N-substituted benzylamines of TableV are obtained.

                                      Table V                                     __________________________________________________________________________         Example                                                                       in which                                                                      the benzyl-                                                                   bromide                                                                       used is                                                                             Amine used in                                                      Ex. No.                                                                            described                                                                           the reaction                                                                           Reaction product Mp °C.                            __________________________________________________________________________    111  62    allylamine                                                                             (3-amino-4-phenoxy-5-sulfamyl-                                                benzyl)allylamine hydrate                                                                       95-98                                   112  63    isopentylamine                                                                         (3-methylamino-4-phenoxy-5-                                                   sulfamylbenzyl)isopentylamine                                                 hydrate           86-88                                   113  65    isopropylamine                                                                         (3-allylamino-4-phenoxy-5-                                                    sulfamylbenzyl)isopropylamine                                                                   97-100                                  114  66    isopropylamine                                                                         (4-phenoxy-3-propargylamino-                                                  5-sulfamylbenzyl)isopropyl-                                                   amine            155-157                                  115  67    methylamine                                                                            (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)methylamine                                                                     156-158                                  116  67    ethylamine                                                                             (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)ethylamine                                                                      152-153                                  117  67    n-propylamine                                                                          (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)-n-propylamine                                                                  127-129                                  118  67    isopropylamine                                                                         (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)isopropylamine                                                                  131-133                                  119  67    n-butylamine                                                                           (3-n-butylamino-4-phenoxy-5-                                                  Sulfamylbenzyl)-n-butylamine                                                                   108-110                                  120  67    isobutylamine                                                                          (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)isobutylamine                                                                   126-127                                  121  67    sec-butylamine                                                                         (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)sec-butylamine                                                                  162-163                                  122  67    tert-butylamine                                                                        (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)tert-butyl-                                                    amine hydrate    109-111                                  123  67    n-hexylamine                                                                           (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)-n-hexylamine                                                                    74-76                                   124  67    allylamine                                                                             (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)allylamine                                                                      111-113                                  125  67    2-methylallyl-                                                                         (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-2-methyl-                                                     allylamine        63-64                                   126  67    dimethylamine                                                                          (3-n-butylamino-4-phenoxy-5-                                         (40% in water)                                                                         sulfamylbenzyl)dimethylamine                                                                    97-98                                   127  67    diethylamine                                                                           (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)diethylamine                                                                    116-117                                  128  67    n-butylmethyl-                                                                         (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-n-butylmethyl-                                                amine            103-105                                  129  67    ethanolamine                                                                           (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)ethanolamine                                                                    182-183                                  130  67    N-methyl-                                                                              N-(3-n-butylamino-4-phenoxy-                                         ethanolamine                                                                           5-sulfamylbenzyl)-N-methyl-                                                   2-hydroxyethylamine                                                                            121-122                                  131  67    3-aminopropanol                                                                        (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-3-hydroxy-                                                  propylamine      163-164                                  132  67    1-amino-2-                                                                             (3-n-butylamino-4-phenoxy-5-                                         propanol sulfamylbenzyl)-2-hydroxy-                                                    propylamine      169-170                                  133  67    2-amino-2-                                                                             (3-n-butylamino-4-phenoxy-5-                                         methyl-1-                                                                              sulfamylbenzyl)-1,1-dimethyl-                                        propanol 2-hydroxyethylamine                                                                            119-121                                  134  67    diethanolamine                                                                         (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)diethanolamine  60-62                      135  67    2-methoxyethyl-                                                                        (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-2-methoxy-                                                    ethylamine       100-101                                  136  67    benzylamine                                                                            (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)benzylamino                                                                      86-87                                   137  67    aminodiphenyl-                                                                         (3-n-butylamino-4-phenoxy-5-                                         methane  sulfamylbenzyl-Δ-phenyl-                                                benzylamine      134-136                                  138  67    4-methoxybenzyl-                                                                       (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-4-methoxy-                                                    benzylamine hydrate                                                                             76-78                                   139  67    2-phenethyl-                                                                           (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-2-phenethyl                                                   amine            128-129                                  140  67    homoveratryl-                                                                          (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)-3,4-dimethoxy-                                                2-phenethylamine hydrate                                                                        76-80                                   141  67    2-phenylthio-                                                                          (3-n-butylamino-4-phenoxy-5-                                         ethylamine                                                                             sulfamylbenzyl)-2-phenylthio-                                                 ethylamine        97-99                                   142  67    2-furfurylamine                                                                        (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-2-furfuryl-                                                 amine            104-105                                  143  67    2-tetrahydro-                                                                          (3-n-butylamino-4-phenoxy-5-                                         furfurylamine                                                                          sulfamylbenzyl)-2-tetrahydro-                                                 furfurylamine    114-116                                  144  67    N-methyl-2-                                                                            N-(3-n-butylamino-4-phenoxy-                                         furfurylamine                                                                          5-sulfamylbenzyl)-N-methyl-                                                   2-furfurylamine   79-81                                   145  67    N-methyl-2-                                                                            N-(3-n-butylamino-4-phenoxy-                                         tetrahydro-                                                                            5-sulfamylbenzyl)-N-methyl-2-                                        furfurylamine                                                                          tetrahydrofurfurylamine                                                                        127-128                                  146  67    2-picolylamine                                                                         (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)-2-picolylamine                                                                 112-114                                  147  68    isopropylamine                                                                         (3-n-pentylamino-4-phenoxy-5-                                                 sulfamylbenzyl)isopropylamine                                                                  116-117                                  148  69    n-pentylamine                                                                          (3-isopentylamino-4-phenoxy-                                                  5-sulfamylbenzyl-n-pentyl-                                                    amine hemihydrate                                                                              100-103                                  149  70    dimethylamine                                                                          (3-benzylamino-4-phenoxy-5-                                                   sulfamylbenzyl)dimethylamine                                                                   156-158                                  150  70    allylamine                                                                             (3-benzylamino-4-phenoxy-5-                                                   sulfamylbenzyl)allylamine                                                                      139-141                                  151  70    n-butylamine                                                                           (3-benzylamino-4-phenoxy-5-                                                   sulfamylbenzyl)-n-butylamine                                                                   108-110                                  152  70    benzylamine                                                                            (3-benzylamino-4-phenoxy-5-                                                   sulfamylbenzyl)benzylamine                                                                     129-131                                  153  73    isopropylamine                                                                         (3-n-butyalmino-4-(4'-methoxy-                                                phenoxy)-5-sulfamylbenzyl)iso-                                                propylamine hydrate                                                                             91-94                                   154  74    allylamine                                                                             (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)allyl-                                              amine            166-167                                  155  74    benzylamine                                                                            (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)-                                                   benzylamine      181-183                                  156  75    dimethylamine                                                                          (3-benzylamino-4-(3'-trifluoro-                                               methylphenoxy)-5-sulfamylbenzyl)-                                             dimethylamine dihydrate                                                                         97-100                                  157  76    isopropylamine                                                                         (3-n-butylamino-4-phenylthio-5-                                               sulfamylbenzyl)isopropylamine                                                                  130-131                                  158  76    allylamine                                                                             (3-n-butylamino-4-phenylthio-                                                 5-sulfamylbenzyl)allylamine                                                                    124-126                                  159  77    isopropylamine                                                                         (3-benzylamino-4-phenylthio-                                                  5-sulfamylbenzyl)isopropyl-                                                   amine hydrate     57-59                                   160  77    allylamine                                                                             (3-benzylamino-4-phenylthio-5-                                                sulfamylbenzyl)allylamine                                                                      118-119                                  161  77    benzylamine                                                                            (3-benzylamino-4-phenylthio-                                                  5-sulfamylbenzyl)benzylamine                                                                   100-102                                  162  79    3-picolylamine                                                                         (3-benzylamino-4-(2'-methyl-                                                  phenylthio)-5-sulfamylbenzyl)-                                                3-picolylamine dihydrate                                                                        96-99                                   163  80    isopropylamine                                                                         (4-anilino-3-n-butylamino-5-                                                  sulfamylbenzyl)isopropylamine                                                                  123-125                                  164  80    allylamine                                                                             (4-anilino-3-n-butylamino-5-                                                  sulfamylbenzyl)allylamine                                                                      163-165                                  165  81    allylamine                                                                             (4-anilino-3-benzylamino-5-                                                   sulfamylbenzyl)allylamine                                                                      192-194                                  166  81    benzylamine                                                                            (4-anilino-3-benzylamino-5-                                                   sulfamylbenzyl)benzylamine                                                                     153-156                                  167  83    isopropylamine                                                                         (3-benzylamino-4-(4'-chloro-                                                  anilino)-5-sulfamylbenzyl)iso-                                                propylamine      190-191                                  168  83    allylamine                                                                             (3-benzylamino-4-(4'-chloro-                                                  anilino)-5-sulfamylbenzyl)allyl-                                              amine            163-164                                  169  83    benzylamine                                                                            (3-benzylamino-4-(4'-chloro-                                                  anilino)-5-sulfamylbenzyl)ben-                                                zylamine         153-155                                  170  61    benzylamine                                                                            (3-amino-4-benzyl-5-sulfamyl-                                                 benzyl)benzylamine, sesqui-                                                   hydrate           61-63                                   171  84    methylamine                                                                            (4-benzyl-3-ethylamino-5-sulf-                                                amylbenzyl)methylamine hemi-                                                  hydrate          101-103                                  172  85    dimethylamine                                                                          (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)dimethylamine                                                                   112-113                                  173  85    allylamine                                                                             (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)allylamine                                                                      154-155                                  174  85    n-butylamine                                                                           (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)-n-butylamine                                                                   139-141                                  175  85    benzylamine                                                                            (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)benzylamine                                                    hemihydrate      103-105                                  176  86    dimethylamine                                                                          (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)dimethylamine                                                  hydrate           79-81                                   177  86    allylamine                                                                             (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)allylamine                                                                      141-143                                  178  86    n-butylamine                                                                           (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)-n-butylamine                                                                   139-140                                  179  86    benzylamine                                                                            (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)benzylamine                                                                     140-141                                  180  54    dimethylamine                                                                          (4-benzyl-3-n-butoxy-5-sulfamyl-                                              benzyl)dimethylamine                                                                           110-111                                  181  54    allylamine                                                                             (4-benzyl-3-n-butoxy-5-sulfamyl-                                              benzyl)allylamine                                                                              117-118                                  182  54    isopropylamine                                                                         (4-benzyl-3-n-butoxy-5-sulfamyl-                                              benzyl)isopropylamine                                                                          138-140                                  183  54    n-butylamine                                                                           (4-benzyl-3-n-butoxy-5-sulfamyl-                                              benzyl)-n-butylamine                                                                           120-123                                  184  54    benzylamine                                                                            (4-benzyl-3-n-butoxy-5-sulfamyl-                                                                86-87                                                       benzyl)benzylamine                                        185  53    dimethylamine                                                                          (4-benzyl-3-methylthio-5-                                                     sulfamylbenzyl)dimethylamine                                                  hydrate           88-91                                   186  55    4-picolylamine                                                                         (4-benzyl-3-ethylthio-5-sulfamyl-                                             benzyl)-4-picolylamine                                                                         110-112                                  187  56    n-hexylamine                                                                           (3-allylthio-4-benzyl-5-                                                      sulfamylbenzyl)-n-hexylamine                                                  hydrate           90-93                                   188  57    isopropylamine                                                                         (4-benzyl-3-n-butylthio-5-                                                    sulfamylbenzyl)isopropylamine                                                                  157-159                                  189  57    allylamine                                                                             (4-benzyl-3-n-butylthio-5-                                                    sulfamylbenzyl)allylamine                                                                      140-142                                  190  59    n-butylamine                                                                           (4-benzyl-3-(2'-phenethylthio)-                                               5-sulfamylbenzyl)-n-butylamine                                                dihydrate         96-100                                  __________________________________________________________________________

EXAMPLE 191. (3-Ethylamino-4-phenoxy-5-sulfamylbenzyl)benzylaminehydrochloride.

A mixture of 3-ethylamino-4-phenoxy-5-sulfamylbenzyl bromidehydrobromide (2.5 g; prepared as described in Example 64), benzylamine(10 ml) and methanol (20 ml) is stirred at 22°-25° C. for 24 hours. Theresulting solution is then diluted with water (60 ml) to precipitate(3-ethylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine as an oil. The oilis separated and dissolved in ethanol (20 ml), whereafter a saturatedsolution of dry hydrogen chloride in ethanol (2 ml) is added toprecipitate the hydrochloride. After filtration and recrystallizationfrom ethanol, (3-ethylamino-4-phenoxy-5-sulfamylbenzyl)benzylaminehydrochloride is obtained with a melting point of 220°-223° C.

EXAMPLES 192-215.

By following the procedure described in Example 191 but using asstarting materials the appropriate 4-R₁ -3-R₂ -5-sulfamylbenzyl bromide(pr hydrobromide) and amine as defined in Table VI below, thecorresponding 4-R₁ -3-R₂ -5-sulfamyl N-substituted benzylaminehydrochlorides of Table VI are obtained.

                                      Table VI                                    __________________________________________________________________________         Example                                                                       in which                                                                      the benzyl-                                                                   bromide                                                                       used is                                                                             Amine used in                                                      Ex. No.                                                                            described                                                                           the reaction                                                                           Reaction product Mp °C.                            __________________________________________________________________________    192  67    isopentylamine                                                                         (3-n-butylamino-4-phenoxy-5-                                                                   211-213                                                      sulfamylbenzyl)isopentylamine                                                 dihydrochloride                                           193  67    cyclohexyl-                                                                            (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)cyclohexylamine                                                hydrochloride    238-239                                  194  67    di-n-propyl-                                                                           (3-n-butylamino-4-phenoxy-5-                                         amine    sulfamylbenzyl)di-n-propyl-                                                   amine hydrochloride                                                                            218-220                                  195  67    N-ethylcyclo-                                                                          N-(3-n-butylamino-4-phenoxy-                                         hexylamine                                                                             5-sulfamylbenzyl)-N-ethylcyclo-                                               hexylamine hydrochloride                                                                       164-166                                  196  67    2-ethylamino-                                                                          N-(3-n-butylamino-4-phenoxy-                                         ethanol  5-sulfamylbenzyl)-N-ethyl-2-                                                  hydroxyethylamine hydrochlo-                                                  ride hydrate     156-157                                  197  67    2-isopropyl-                                                                           N-(3-n-butylamino-4-phenoxy-                                         aminoethanol                                                                           5-sulfamylbenzyl)-N-isopropyl-                                                2-hydroxyethylamine hydrochlo-                                                ride hydrate     150-152                                  198  67    2-diethylamino-                                                                        (3-n-butylamino-4-phenoxy-5-                                         ethylamine                                                                             sulfamylbenzyl)-2-diethyl-                                                    aminoethylamine dihydrochlo-                                                  ride             205-206                                  199  67    N-benzylmethyl-                                                                        N-(3-n-butylamino-4-phenoxy-                                         amine    5-sulfamylbenzyl)-N-benzyl-                                                   methylamine hydrochloride                                                                      219-220                                  200  67    3-chloro-                                                                              (3-n-butylamino-4-phenoxy-5-                                         benzylamine                                                                            sulfamylbenzyl)-3-chlorobenzyl-                                               amine hydrochloride hydrate                                                                    106-108                                  201  67    dibenzylamine                                                                          (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)dibenzylamine                                                  hydrochloride    208-210                                  202  67    3-piperidino-                                                                          (3-n-butylamino-4-phenoxy-                                           propylamine                                                                            5-sulfamylbenzyl)-3-piperidino-                                               propylamine dihydrochloride                                                   trihydrate       138-140                                  203  71    diethylamine                                                                           (4-phenoxy-3-(2'-pyridylmethyl-                                               amino)-5-sulfamylbenzyl)di-                                                                    above                                                        ethylamine dihydrochloride                                                                     260                                      204  72    isopropyl-                                                                             (4-phenoxy-3-(3'-pyridyl-                                            amine    methylamino)-5-sulfamylben-                                                   zyl)isopropylamine dihydro-                                                                    above                                                        chloride         260                                      205  78    methylamine                                                                            (3-n-butylamino-4-(2'-methyl-                                        (40% in water)                                                                         phenylthio)-5-sulfamylbenzyl)                                                 methylamine hydrochloride                                                                      210-212                                  206  82    n-propylamine                                                                          (3-n-butylamino-4-(4'-chloro-                                                 anilino)-5-sulfamylbenzyl)-                                                   n-propylamine hydrochloride                                                                    222-224                                  207  87    crotylamine                                                                            (4-phenoxy-3-(4'-pyridylethyl-                                                (2)-amino)-5-sulfamylbenzyl)-                                                                  above                                                        crotylamine dihydrochloride                                                                    260                                      208  88    isobutylamine                                                                          (3-benzylamino-4-phenylsulfi-                                                 nyl-5-sulfamylbenzyl)isobutyl-                                                amine hydrochloride                                                                            210-213                                  209  61    dimethylamine                                                                          (3-amino-4-benzyl-5-sulfamyl-                                                 benzyl)dimethylamine dihydro-                                                 chloride hemihydrate                                                                           216-218                                  210  54    veratrylamine                                                                          (4-benzyl-3-n-butoxy-5-sulf-                                                  amylbenzyl)-3,4-dimethoxybenzyl-                                              amine hydrochloride hydrate                                                                    161-163                                  211  57    benzylamine                                                                            (4-benzyl-3-n-butylthio-5-                                                    sulfamylbenzyl)benzylamine                                                    hydrochloride    116-117                                  212  58    isopropyl-                                                                             (4-benzyl-3-benzylthio-5-                                            amine    sulfamylbenzyl)isopropylamine                                                 hydrochloride    183-185                                  213  58    allylamine                                                                             (4-benzyl-3-benzylthio-5-                                                     sulfamylbenzyl)allylamine                                                     hydrochloride    189-191                                  214  58    benzylamine                                                                            (4-benzyl-3-benzylthio-5-                                                     sulfamylbenzyl)benzylamine                                                    hydrochloride    178-180                                  215  60    ethylamine                                                                             (4-benzyl-3-(2'-pyridylmethyl-                                                thio)-5-sulfamylbenzyl)ethyl-                                                                  above                                                        amine dihydrochloride                                                                          260                                      __________________________________________________________________________

EXAMPLE 216. (3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)aniline.

A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzyl bromidehydrobromide (2.5 g; prepared as described in Example 67) and aniline(10 ml) in methanol (20 ml) is refluxed for 16 hours. After cooling themixture is diluted with water (about 80 ml); the resulting semi-solidprecipitate is washed twice with water, which is decanted, and is thencrystallized from aqueous ethanol. After filtration andrecrystallization from ethanol,(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)aniline is obtained with amelting point of 142°-143° C.

EXAMPLES 217-230.

By following th procedure described in Example 216 but using as startingmaterials the appropriate 4-R₁ -3-R₂ -5-sulfamylbenzyl bromide (orhydrobromide) and amine as defined in Table VII below, the corresponding4-R₁ -3-R₂ -5-sulfamyl N-substituted benzylamines of Table VII areobtained.

                                      Table VII                                   __________________________________________________________________________         Example                                                                       in which                                                                      the benzyl-                                                                   bromide                                                                       used is                                                                             Amine used in                                                      Ex. No.                                                                            described                                                                           the reaction                                                                          Reaction product                                                                             Mp °C.                               __________________________________________________________________________    217  65    aniline (3-allylamino-4-phenoxy-5-                                                    sulfamylbenzyl)aniline                                                                       118-119                                     218  66    aniline (4-phenoxy-3-propargylamino-                                                  5-sulfamylbenzyl)aniline                                                                     125-126                                     219  67    o-toluidine                                                                           (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)-2-methyl-                                                     aniline        142-144                                     220  67    2,6-dimethyl-                                                                         (3-n-butylamino-4-phenoxy-                                            aniline 5-sulfamylbenzyl)-2,6-dimethyl-                                               aniline        125-127                                     221  67    m-fluoro-                                                                             (3-n-butylamino-4-phenoxy-5-                                          aniline sulfamylbenzyl)-3-fluoro-                                                     aniline        156-158                                     222  68    aniline (3-n-pentylamino-4-phenoxy-5-                                                 sulfamylbenzyl)aniline                                                                       142-143                                     223  70    aniline (3-benzylamino-4-phenoxy-5-                                                   sulfamylbenzyl)aniline                                                                       134-136                                     224  74    aniline (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)-                                                   aniline        170-172                                     225  77    aniline (3-benzylamino-4-phenylthio-                                                  5-sulfamylbenzyl)aniline hemi-                                                hydrate         68-70                                      226  81    aniline (4-anilino-3-benzylamino-5-                                                   sulfamylbenzyl)aniline                                                                       173-175                                     227  83    aniline (3-benzylamino-4-(4'-chloro-                                                  anilino)-5-sulfamylbenzyl)-                                                   aniline        164-165                                     228  85    aniline (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)aniline hemi-                                                  hydrate         98-99                                      229  86    aniline (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)aniline                                                                        99-101                                     230  54    aniline (4-benzyl-3-n-butoxy-5-                                                       sulfamylbenzyl)aniline                                                                        77-80                                      __________________________________________________________________________

EXAMPLE 231. (3-Allylamino-4-phenoxy-5-sulfamylbenzyl)isopropylamine.

A mixture of 3-allylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g;prepared as described in Example 91), isopropylamine (4.0 ml) andmethanol (100 ml) is stirred at 22°-25° C. for 24 hours and is thenrefluxed for 2 hours. To the stirred solution, sodium borohydride (4.0g) is added in small portions during about 45 l minutes, keeping thetemperature at 0°-5° C. by external cooling. After the addition iscompleted, the reaction mixture is stirred at 0°-5° C. for a further 2hours, whereafter acetic acid (4 ml) followed by water (300 ml) arecautiously added to precipitate crude(3-allylamino-4-phenoxy-5-sulfamylbenzyl)isopropylamine. Afterfiltration and recrystallization from aqueous ethanol it is obtainedwith a melting point of 98°-100° C. The material (IR, analysis) isidentical with the material prepared as in Example 113.

EXAMPLES 232-288.

By following the procedure described in Example 231 but using asstarting materials the appropriate 4-R₁ -3-R₂ -5-sulfamylbenzaldehydeand amine as defined in Table VIII below, the corresponding 4-R₁ -3-R₂-5-sulfamyl N-substituted benzylamines of Table VIII are obtained.

                                      Table VIII                                  __________________________________________________________________________         Example in                                                                    which the                                                                     benzaldehyde                                                                  used is                                                                              Amine used in                                                     Ex. No.                                                                            described                                                                            the reaction                                                                          Reaction product                                                                              Mp° C.                             __________________________________________________________________________    232   89    cyclopentyl-                                                                          (3-methylamino-4-phenoxy-5-                                           amine   sulfamylbenzyl)cyclopentyl-                                                   amine hydrate    88-92                                    233   90    sec-butylamine                                                                        (3-ethylamino-4-phenoxy-5-                                                    sulfamylbenzyl)sec-butyl-                                                     amine dihydrate  96-98                                    234   91    aniline (3-allylamino-4-phenoxy-5-                                                    sulfamylbenzyl)aniline                                                                        117-119                                   235   92    isopropylamine                                                                        (4-phenoxy-3-propargylamino-                                                  5-sulfamylbenzyl)isopropyl-                                                   amine           155-156                                   236   92    aniline (4-phenoxy-3-propargylamino-                                                  5-sulfamylbenzyl)aniline                                                                      125-127                                   237   93    isobutylamine                                                                         (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)isobutyl-                                                    amine           126-127                                   238   93    aniline (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)aniline                                                                      140-141                                   239   93    o-toluidine                                                                           (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-2-methyl-                                                   aniline         143-144                                   240   93    p-toluidine                                                                           (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-4-methyl-                                                   aniline, ethanol                                                                               95-97                                    241   93    3,4-dimethyl-                                                                         (3-n-butylamino-4-phenoxy-                                            aniline 5-sulfamylbenzyl)-3,4-di-                                                     methylaniline   127-130                                   242   93    o-hydroxy-                                                                            (3-n-butylamino-4-phenoxy-                                            aniline 5-sulfamylbenzyl)-2-hydroxy-                                                  aniline         107- 109                                  243   93    m-hydroxy-                                                                            (3-n-butylamino-4-phenoxy-                                            aniline 5-sulfamylbenzyl)-3-hydroxy-                                                  aniline hydrate 100-102                                   244   93    p-hydroxy-                                                                            (3-n-butylamino-4-phenoxy-                                            aniline 5-sulfamylbenzyl)-4-hydroxy-                                                  aniline         173-174                                   245   93    o-anisidine                                                                           (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-2-methoxy-                                                  aniline         183-184                                   246   93    m-phenetidine                                                                         (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-3-ethoxy-                                                   aniline         161-163                                   247   93    o-trifluoro-                                                                          (3-n-butylamino-4-phenoxy-                                            methylaniline                                                                         5-sulfamylbenzyl)-2-tri-                                                      fluoromethylaniline                                                                           180-181                                   248   93    m-fluoro-                                                                             (3-n-butylamino-4-phenxoy-                                            aniline 5-sulfamylbenzyl)-3-fluoro-                                                   aniline         156-157                                   249   93    m-chloroaniline                                                                       (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-3-chloro-                                                   aniline         145-146                                   250   93    4-chloro-2-                                                                           (3-n-butylamino-4-phenoxy-                                            methylaniline                                                                         5-sulfamylbenzyl)-4-chloro-                                                   2-methylaniline 160-162                                   251   93    p-bromoaniline                                                                        (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-4-bromo-                                                    aniline, ethanol                                                                              146-148                                   252   93    3-aminopyridine                                                                       (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-3-amino-                                                    pyridine        195-195                                   253   93    6-amino-2-                                                                            (3-n-butylamino-4-phenoxy-                                            methylpyridine                                                                        5-sulfamylbenzyl)-6-amino-                                                    2-methylpyridine                                                                              136-138                                   254   94    isopropyl-                                                                            (3-crotylamino-4-phenoxy-                                             amine   5-sulfamylbenzyl)isopropyl-                                                   amine, ethanol  106-109                                   255   94    aniline (3-crotylamino-4-phenoxy-                                                     5-sulfamylbenzyl)aniline                                                                       99-101                                   256   95    isopropyl-                                                                            (3-n-pentylamino-4-phenoxy-                                           amine   5-sulfamylbenzyl)isopropyl-                                                   amine           116-117                                   257   95    aniline (3-n-pentylamino-4-phenoxy-                                                   5-sulfamylbenzyl)aniline                                                                      142-143                                   258   96    isopropyl-                                                                            (3-(2'-furfurylamino)-4-                                              amine   phenoxy-5-sulfamylbenzyl)iso-                                                 propylamine trihydrate                                                                        125-127                                   259   96    allylamine                                                                            (3-(2'-furfurylamino)-4-                                                                      201-203                                                       phenoxy-5-sulfamylbenzyl)-                                                                    (see                                                          allylamine acetate                                                                            below)                                    260   96    benzylamine                                                                           (3-(2'-furfurylamino)-4-                                                                      153-154                                                       phenoxy-5-sulfamylbenzyl)-                                                                    (see                                                          benzylamine acetate                                                                           below)                                    261   96    aniline (3-(2'-furfurylamino)-4-                                                      phenoxy-5-sulfamylbenzyl)-                                                    aniline         155-156                                   262   97    isopropyl-                                                                            (4-phenoxy-5-sulfamyl-3-(2'-                                          amine   thenylamino)benzyl)isopropyl-                                                 amine hemihydrate                                                                             113-115                                   263   97    allylamine                                                                            (4-phenoxy-5-sulfamyl-3-(2'-                                                  thenylamino)benzyl)allylamine                                                 hemihydrate      81-83                                    264   97    benzylamine                                                                           (4-phenoxy-5-sulfamyl-3-(2'-                                                  thenylamino)benzyl)benzyl-                                                    amine           185-187                                   265   97    aniline (4-phenoxy-5-sulfamyl-3-(2'-                                                  thenylamino)benzyl)aniline                                                    hemihydrate      95-97                                    266   98    isopropyl-                                                                            (4-phenoxy-3-(4'-pyridylethyl-                                        amine   (2)-amino)-5-sulfamylbenzyl)iso-                                              propylamine dihydrate                                                                          86-90                                    267   99    aniline (3-n-butylamino-4-(4'-methoxy-                                                phenoxy)-5-sulfamylbenzyl)-                                                   aniline hemihydrate                                                                           102-105                                   268  100    isopropyl-                                                                            (3-benzylamino-4-(4'-methoxy-                                         amine   phenoxy)-5-sulfamylbenzyl)iso-                                                propylamine     193-195                                   269  100    allylamine                                                                            (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)-                                                   allylamine      166-167                                   270  100    benzylamine                                                                           (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)-                                                   benzylamine     182-183                                   271  100    aniline (3-benzylamino-4-(4'-methoxy-                                                 phenoxy)-5-sulfamylbenzyl)-                                                   aniline         171-172                                   272  101    n-butylamine                                                                          (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)-n-butylamine                                                                  139-141                                   273  101    aniline (4-benzyl-3-n-butylamino-5-                                                   sulfamylbenzyl)aniline hemi-                                                  hydrate          98-99                                    274  102    allylamine                                                                            (4-benzyl-3-(2'-furfurylamino)-                                               5-sulfamylbenzyl)allylamine                                                   hydrate          96-98                                    275  102    aniline (4-benzyl-3-(2'-furfurylamino)-                                               5-sulfamylbenzyl)aniline                                                                      148-150                                   276  103    2-phenethyl-                                                                          (4-benzyl-3-methoxy-5-sulfamyl-                                       amine   benzyl)-2-phenethylamine hemi-                                                hydrate         103-105                                   277  104    crotylamine                                                                           (4-benzyl-3-ethoxy-5-sulfamyl-                                                benzyl)crotylamine dihydrate                                                                   87-90                                    278  105    n-propylamine                                                                         (4-benzyl-3-n-propoxy-5-                                                      sulfamylbenzyl)-n-propyl-                                                     amine hemihydrate                                                                             106-108                                   279  106    allylamine                                                                            (4-benzyl-3-isopropoxy-5-                                                     sulfamylbenzyl)allylamine,                                                    sesquihydrate    94-96                                    280  107    isopropyl-                                                                            (4-benzyl-3-n-butoxy-5-                                               amine   sulfamylbenzyl)isopropylamine                                                                 139-141                                   281  107    n-butylamine                                                                          (4-benzyl-3-n-butoxy-5-                                                       sulfamylbenzyl)-n-butylamine                                                                  121-122                                   282  107    veratrylamine                                                                         (4-benzyl-3-n-butoxy-5-                                                                       161-162                                                       sulfamylbenzyl)-3,4-dimethoxy-                                                                (see                                                          benzylamine hydrochloride                                                                     below)                                    283  107    aniline (4-benzyl-3-n-butoxy-5-                                                       sulfamylbenzyl)aniline                                                                         79-80                                    284  108    2-phenethyl-                                                                          (4-benzyl-3-isopentyloxy-5-                                           amine   sulfamylbenzyl)-2-phenethyl-                                                  amine hydrate    82-86                                    285  109    isopropyl-                                                                            (4-benzyl-3-benzyloxy-5-                                                                      213-215                                               amine   sulfamylbenzyl)isopropylamine                                                                 (see                                                          acetate         below)                                    286  109    allylamine                                                                            (4-benzyl-3-benzyloxy-5-                                                      sulfamylbenzyl)allylamine                                                                     123-125                                   287  109    benzylamine                                                                           (4-benzyl-3-benzyloxy-5-                                                                      144-146                                                       sulfamylbenzyl)benzylamine                                                                    (see                                                          acetate         below)                                    288  109    aniline (4-benzyl-3-benzyloxy-5-                                                      sulfamylbenzyl)aniline                                                                        134-136                                   __________________________________________________________________________

The materials prepared as in Examples 234, 235, 236, 237, 238, 239, 248,256, 257, 269, 270, 271, 272, 273, 280, 281, 282 and 283 are identical(IR, analysis) with the materials prepared as in Examples 217, 114, 218,120, 216, 219, 221, 147, 222, 154, 155, 224, 174, 228, 182, 183, 210 and230 respectively. The compounds of Examples 259, 260, 285 and 287 areisolated as acetates, while the compound of Example 282 is converted tothe hydrochloride following the procedure described in Examples 191.

EXAMPLE 289. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylamine.

To a mixture of lithium aluminium hydride (1.6 g) and drytetrahydrofuran (10 ml), a solution of3-n-butylamino-4-phenoxy-5-sulfamylbenzamide (2.25 g) in dry pyridine(20 ml) is added, and the mixture is refluxed for 16 hours. Aftercooling, ethyl acetate (1 ml) followed by water (6 ml) are verycautiously added dropwise, whereafter the mixture is stirred for afurther 30 minutes. It is then heated on a steambath and filtered hot;the filter-cake is carefully washed with hot 2-methoxyethanol (3portions of 20 ml). The combined filtrates are evaporated in vacuo andthe residue is crystallized from ethanol to give3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine with a melting point of195°-198° C.

EXAMPLE 290. (3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine

By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamidewith an equimolar amount of3-n-butylamino-4-phenoxy-5-sulfamyl-N-methylbenzamide and following theprocedure described,(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine is obtained witha melting point of 157°-159° C. The material (IR, analysis) is identicalwith the material prepared as in Example 115.

EXAMPLE 291. (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine.

A. 4-Benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide.

A mixture of 4-benzyl-3-n-butoxy-5-sulfamylbenzoic acid (3.6 g), thionylchloride (20 ml) and N,N-dimethylformamide (0.1 ml) is refluxed for 1hour and is then evaporated in vacuo. The resulting crude4-benzyl-3-n-butoxy-5-sulfamylbenzoyl chloride is dissolved in methylenechloride (30 ml), and the resulting solution is during about 15 minutesadded dropwise to a stirred mixture of dimethylamine (10 ml; 40% inwater) and methylene chloride (20 ml), keeping the temperature at 0°-5°C. by external cooling. After stirring for an additional 2 hours at22°-25° C., the mixture is washed with water and the organic layer isseparated and dried in the presence of magnesium sulphate. Filtrationfollowed by evaporation in vacuo yields crude4-benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide. Afterrecrystallization from benzene it is obtained with a melting point of199°-201° C.

B. (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine.

By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamidewith an equimolar amount of4-benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide and following theprocedure described, (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamineis obtained with a melting point of 110°-111° C. The material (IR,analysis) is identical with the material prepared as in Example 180.

EXAMPLE 292.(4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)-2-diethylaminoethylamine.

A. 4-Benzyl-3-n-butoxy-5-sulfamyl-N-(2'-diethylaminoethyl)benzamide.

By replacing in Example 291, step A, dimethylamine with an equimolaramount of 2-diethylaminoethylamine and following the proceduredescribed,4-benzyl-3-n-butoxy-5-sulfamyl-N-(2'-diethylaminoethyl)benzamide isobtained with a melting point of 163° C.

B. (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)-2-diethylaminoethylamine.

By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamidewith an equimolar amount of4-benzyl-3-n-butoxy-5-sulfamyl-N-(2'-diethylaminoethyl)-benzamide andfollowing the procedure described,(4-benzyl-3-n-butoxy-5-sulfamylbenzyl)-2-diethylaminoethylamine isobtained as a dihydrate with a melting point of 89°-93° C.

EXAMPLE 293.(4-benzyl-3-n-butoxy-5-sulfamylbenzyl)-3-piperidinopropylamine.

A. 4-Benzyl-3-n-butoxy-5-sulfamyl-N-(3'-piperidinopropyl)benzamide.

By replacing in Example 291, step A, dimethylamine with an equimolaramount of 3-piperidinopropylamine and following the procedure described,4-benzyl-3-n-butoxy-5-sulfamyl-N-(3'-piperidinopropyl)benzamide isobtained with a melting point of 138° C.

B. (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)-3-piperidinopropylamine.

By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamidewith an equimolar amount of4-benzyl-3-n-butoxy-5-sulfamyl-N-(3'-piperidinopropyl)benzamide andfollowing the procedure described,(4-benzyl-3-n-butoxy-5-sulfamylbenzyl)-3-piperidinopropylamine isobtained as a hemihydrate with a melting point of 98°-101° C.

EXAMPLE 294. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylaminehydrochloride.

A. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzaldoxime

To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g;prepared as in Example 93) in hot methanol (100 ml) a solution ofhydroxylamine hydrochloride (10 g) and ammonium acetate (10 g) in water(25 ml) is added, and the mixture is left for 3 days. Water (500 ml) isthen added, and the resulting precipitate is collected by filtration,washed with water and dried in air. After recrystallization from amixture of ethanol and 2-methoxyethanol,3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime is obtained with amelting point of 226°-228° C.

B. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylamine hydrochloride.

A mixture of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime (3.6 g),stannous chloride dihydrate (12 g), concentrated hydrochloric acid (25ml) and acetic acid (50 ml) is heated on a steam-bath for 2-3 hours.After concentration in vacuo to about 50 ml,3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine hydrochloride starts tocrystallize from the solution. After cooling, the hydrochloride iscollected by filtration, washed with ethanol and dried in air. Afterrecrystallization from 2-methoxyethanol it is obtained with a meltingpoint higher than 300° C.

EXAMPLE 295. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylamine.

A. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzonitrile.

A mixture of 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide (8.5 g) andphosphorus oxychloride (25 ml) is heated at 120° C. for 2 hours. Themixture is then evaporated in vacuo and the residue is triturated withice-water (120 ml) to yield crude3-n-butylamino-4-phenoxy-5-sulfamylbenzonitrile. After filtration,carefully washing with water, drying and recrystallization frommethanol, it is obtained with a melting point of 217°-218° C.

B. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylamine.

To a stirred mixture of lithium aluminium hydride (5.0 g) and1,2-dimethoxyethane (100 ml) a solution of3-n-butylamino-4-phenoxy-5-sulfamylbenzonitrile (15 g) in dry1,2-dimethoxyethane (150 ml) is during about one hour at 100° C.dropwise added, and the mixture is stirred and refluxed for a further 16hours. After cooling, ethyl acetate (10 ml) followed by water (20 ml)are very cautiously added dropwise, whereafter the mixture is stirredfor a further 30 minutes. It is then heated on a steam-bath and filteredhot; the filter-cake is carefully washed with hot 2-methoxyethanol (3portions of 50 ml). The combined filtrates are evaporated in vacuo toyield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. Afterrecrystallization from 2-methoxyethanol it is obtained with a meltingpoint of 197°-198° C. The material (IR, analysis) is identical with thematerial prepared as in Example 289.

EXAMPLE 296. 3-n-Butylamino-4-phenoxy-5-sulfamylbenzylamine formatehemihydrate

To a solution of (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine(8.8 g; prepared as described in Example 136) in 2-methoxyethanol (90ml), palladium (10%) on carbon (4.0 g) is added and the mixture ishydrogenated. After about 5 hours the theoretical amount of hydrogen hasbeen absorbed, and the mixture is heated on a steam-bath and filtered toremove the catalyst. The filtrate is evaporated in vacuo and the residuetriturated with water to yield crude3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. The crude amine isdissolved in formic acid (50 ml), whereafter the solution is evaporatedin vacuo. The residue is recrystallized from a mixture of ethanol and2-methoxyethanol to yield, after filtration and drying,3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine formate hemihydrate witha melting point of 224°-226° C.

EXAMPLE 297. 4-Benzyl-3-n-butoxy-5-sulfamylbenzylamine hydrochloridehydrate.

By replacing in Example 296(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine with an equimolaramount of (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)benzylamine (prepared asdescribed in Example 184) and following the hydrogenation proceduredescribed, crude 4-benzyl-3-n-butoxy-5-sulfamylbenzylamine is obtained.The crude amine is dissolved in ethanol (50 ml) and a saturated solutionof dry hydrogen chloride in ethanol (2 ml) is added to precipitate,after cooling, 4-benzyl-3-n-butoxy-5-sulfamylbenzylamine hydrochloride.After filtration and recrystallization from ethanol it is obtained as ahydrate with a melting point of 176°-179° C.

EXAMPLE 298.(3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)-n-butylmethylamine.

To a stirred mixture of(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine (3.6 g; preparedas described in Example 115), sodium hydrogen carbonate (0.9 g) andhexamethylphosphoric triamide (15 ml) a solution of n-butyl iodide (1.85g) in hexamethylphosphoric triamide (5 ml) is dropwise added duringabout one hour. After additional stirring for 30 minutes, the mixture isdiluted with water to precipitate crude(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-n-butylmethylamine. Afterfiltration and recrystallization twice from ethanol it is obtained witha melting point of 103°-104° C. The material (IR, analysis) is identicalwith the material prepared as in Example 128.

EXAMPLES 299-302.

By following the procedure described in Example 298 but using asstarting materials equimolar amounts of the appropriate 4-R₁ -3-R₂-5-sulfamyl N-substituted benzylamine and alkyl halogenide as defined inTable IX below, the corresponding 4-R₁ -3-R₂ -5-sulfamylN,N-disubstituted benzylamines of Table IX are obtained.

                                      Table IX                                    __________________________________________________________________________         Example in                                                                    which the                                                                            Alkyl                                                                  benzylamine                                                                          halogenide                                                             used is                                                                              used in the                                                       Ex. No.                                                                            described                                                                            reaction                                                                              Reaction product                                                                             Mp °C.                              __________________________________________________________________________    299  116    ethyl iodide                                                                          (3-n-butylamino-4-phenoxy-                                                                   116-117                                                        5-sulfamylbenzyl)diethyl-                                                     amine                                                     300  117    n-propyl iodide                                                                       (3-n-butylamino-4-phenoxy-                                                                   218-219                                                        5-sulfamylbenzyl)di-n-                                                                       (see                                                           propylamine hydrochloride                                                                    below)                                     301  129    isopropyliodide                                                                       N-(3-n-butylamino-4-phenoxy-                                                                 150-152                                                        5-sulfamylbenzyl)-N-iso-                                                                     (see                                                           propyl-2-hydroxyethylamine                                                                   below)                                                         hydrochloride hydrate                                     302  115    benzyl bromide                                                                        N-(3-n-butylamino-4-phenoxy-                                                                 218-220                                                        5-sulfamylbenzyl)-N-benzyl-                                                                  (see                                                           methylamine hydrochloride                                                                    below)                                     __________________________________________________________________________

The materials prepared as in Examples 299, 300, 301 and 302 areidentical (IR, analysis) with the materials prepared as in Examples 127,194, 197 and 199 respectively. The compounds of Examples 300, 301 and302 are converted to the hydrochlorides according to the methoddescribed in Example 191.

EXAMPLE 303(3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)-3-hydroxybenzylamine.

A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g;prepared as described in Example 289) and m-hydroxybenzaldehyde (0.45 g)in methanol (7 ml) is refluxed for 16 hours. The resulting solution iscooled to 0°-5° C. whereafter sodium borohydride (0.25 g) is added inportions during 5 minutes while stirring. After stirring at 22°-25° C.for a further 3 hours, acetic acid (0.5 ml) followed by water (20 ml)are added to precipitate crude(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-3-hydroxybenzylamine. Afterfiltration and recrystallization from ethanol, it is obtained with amelting point of 174°-175° C.

EXAMPLES 304-311

By following the procedure described in Example 303 but using asstarting materials equimolar amounts of the appropriate 4-R₁ -3-R₂-5-sulfamylbenzylamine and aldehyde as defined in Table X below, thecorresponding 4-R₁ -3-R₂ -5-sulfamyl N-substituted benzylamines of TableX are obtained.

                                      Table X                                     __________________________________________________________________________         Example in                                                                    which the                                                                     benzylamine                                                                   used is                                                                              Aldehyde used                                                     Ex. No.                                                                            described                                                                            in the reaction                                                                       Reaction product                                                                             Mp °C.                              __________________________________________________________________________    304  289    benzaldehyde                                                                          (3-n-butylamino-4-phenoxy-5-                                                  sulfamylbenzyl)benzylamine                                                                    86-87                                     305  289    p-methylbenzal-                                                                       (3-n-butylamino-4-phenoxy-5-                                          dehyde  sulfamylbenzyl)-4-methyl-                                                     benzylamine     64-66                                     306  289    p-methoxy-                                                                            (3-n-butylamino-4-phenoxy-                                            benzaldehyde                                                                          5-sulfamylbenzyl)-4-methoxy-                                                  benzylamine hydrate                                                                           77-78                                     307  289    furfural                                                                              (3-n-butylamino-4-phenoxy-                                                    5-sulfamylbenzyl)-2-furfuryl-                                                 amine          103-105                                    308  289    pyridine-3-                                                                           (3-n-butylamino-4-phenoxy-                                                                   263-265                                                aldehyde                                                                              5-sulfamylbenzyl)-3-picolyl-                                                                 (see                                                           amine dihydrochloride hemi-                                                                  below)                                                         hydrate                                                   309  289    pyridine-4-                                                                           (3-n-butylamino-4-phenoxy-                                            aldehyde                                                                              5-sulfamylbenzyl)-4-picolyl-                                                  amine          193-194                                    310  297    benzaldehyde                                                                          (4-benzyl-3-n-butoxy-5-                                                       sulfamylbenzyl)benzylamine                                                                    86-87                                     311  297    veratraldehyde                                                                        (4-benzyl-3-n-butoxy-5-                                                                      162-163                                                        sulfamylbenzyl)-3,4-dimethoxy-                                                               (see                                                           benzylamine hydrochloride                                                                    below)                                                         hydrate                                                   __________________________________________________________________________

The materials prepared as in Examples 304, 306, 307, 310 and 311 areidentical (IR, analysis) with the materials prepared as in Examples 136,138, 142, 184 and 210 respectively. The compounds of Examples 308 and311 are converted to the hydrochlorides according to the proceduredescribed in Example 191.

EXAMPLE 312 N-(3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide.

To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g;prepared as described in Example 289) in acetic acid (10 ml), aceticanhydride (0.4 ml) is added and the mixture is left for 24 hours.Dilution with water (25 ml) precipitatesN-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide, which iscollected by filtration, washed with water and dried in air. Afterrecrystallization from aqueous ethanol it is obtained with a meltingpoint of 190°-191° C.

EXAMPLE 313 N-(3-n-Butylamino-4-phenoxy-5-sulfamylbenzyl)urethan.

To a stirred solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine(1.05 g; prepared as described in Example 289) in pyridine (7 ml) ethylchloroformate (0.3 ml) is dropwise added at 22°-25° C., and the mixtureis stirred for a further 1.5 hours. The mixture is then diluted withwater (30 ml) and acetic acid (10 ml) to precipitate crudeN-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan. After filtrationand recrystallization from ethanol it is obtained with a melting pointof 105°-107° C.

EXAMPLE 314N-Benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide.

To a solution of (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine(1.1 g; prepared as described in Example 136) in pyridine (6 ml), aceticanhydride (0.26 ml) is added and the mixture is left for 3 hours. Water(25 ml) is then added followed by concentrated hydrochloric acid (3 ml)to precipitate a semi-solid material. After recrystallization twice fromaqueous ethanol,N-benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide isobtained with a melting point of 75°-77° C.

EXAMPLE 315N-Benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)isobutyrylamide.

By replacing in Example 314 acetic anhydride with an equimolar amount ofisobutyric anhydride and following the procedure described,N-benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)isobutyrylamide isobtained with a melting point of 118°-120° C.

EXAMPLE 316N-Benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzamide.

By replacing in Example 314 acetic anhydride with an equimolar amount ofbenzoyl chloride and following the procedure described,N-benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzamide isobtained with a melting point of 137°-138° C.

EXAMPLE 317N-Benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan.

By replacing in Example 314 acetic anhydride with an equimolar amount ofethyl chloroformate and following the procedure described,N-benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan isobtained with a melting point of 82°-83° C.

EXAMPLES 318-320

By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamidewith equimolar amounts of the amides defined in Table XI below andfollowing the procedure described, the 4-R₁ -3-R₂ -5-sulfamylN-substituted benzylamines of Table XI are obtained.

                                      Table XI                                    __________________________________________________________________________         Example in which the                                                     Ex. No.                                                                            amide used is described                                                                   Reaction product                                                                              Mp °C.                                __________________________________________________________________________    318  312         (3-n-butylamino-4-phenoxy-5-                                                                  152-153                                                       sulfamylbenzyl)ethylamine                                    319  314         N-(3-n-butylamino-4-phenoxy-                                                                   86-89                                                        5-sulfamylbenzyl)-N-benzylethyl-                                              amine hydrate                                                320  316         (3-n-butylamino-4-phenoxy-5-                                                                  207-210                                                       sulfamylbenzyl)dibenzylamine                                                                  (see                                                          hydrochloride   below)                                       __________________________________________________________________________

The materials prepared as in Examples 318 and 320 are identical (IR,analysis) with the materials prepared as in Examples 116 and 201respectively. The compound of Example 320 is converted to thehydrochloride according to the procedure described in Example 191.

EXAMPLE 321 (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine.

A. 5-Amino-4-benzyl-3-n-butoxybenzyl alcohol.

By replacing in Example 4 methyl 3-amino-4-benzyl-5-sulfamylbenzoatewith an equimolar amount of methyl 5-amino-4-benzyl-3-n-butoxybenzoate(mp 82°-83° C.) and following the procedure described,5-amino-4-benzyl-3-n-butoxybenzyl alcohol is obtained with a meltingpoint of 105°-107° C.

B. 5-Amino-4-benzyl-3-n-butoxybenzyl bromide hydrobromide.

By replacing in Example 61 3-amino-4-benzyl-5-sulfamylbenzyl alcoholwith 5-amino-4-benzyl-3-n-butoxybenzyl alcohol and following theprocedure described, 5-amino-4-benzyl-3-n-butoxybenzyl bromidehydrobromide is obtained with a melting point of 159°-162° C.

C. (5-Amino-4-benzyl-3-n-butoxybenzyl)dimethylamine.

By replacing in Example 110 3-amino-4-benzyl-5-sulfamylbenzylbromidehydrobromide and n-butylamine with 5-amino-4-benzyl-3-n-butoxybenzylbromide hydrobromide and dimethylamine (40% in water) respectively, andfollowing the procedure described,(5-amino-4-benzyl-3-n-butoxybenzyl)dimethylamine is obtained as asemi-solid material.

D. (4-Benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine.

To a stirred solution of(5-amino-4-benzyl-3-n-butoxybenzyl)dimethylamine (6.25 g) in a mixtureof concentrated hydrochloric acid (10 ml) and acetic acid (10 ml) asolution of sodium nitrite (1.4 g) in water (5 ml) is dropwise addedduring 30 minutes, keeping the temperature at 0°-3° C. by externalcooling. After additional stirring at 0° C. for 10 minutes, theresulting diazonium-solution is slowly added to a solution or cupricchloride dihydrate (1.5 g) in water (4 ml) and acetic acid (25 ml)saturated with dry sulphur dioxide while stirring at 22°-25° C. Afterstirring for a further 1 hour, the mixture is cooled to precipitatecrude (4-benzyl-3-n-butoxy-5-chlorosulfonylbenzyl)dimethylaminehydrochloride. The hydrochloride is collected by filtration and washedwith a minor amount of ice-cold acetic acid. It is then added inportions to a stirred, saturated solution of dry ammonia in methanol (30ml) keeping the temperature at 10°-12° C. by external cooling. Theresulting solution is stirred for 16 hours at 22°-25° C. and is thendiluted with water (100 ml) to precipitate crude(4-benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine. After filtrationand recrystallization twice from aqueous ethanol it is obtained with amelting point of 109°-111° C. The material (IR, analysis) is identicalwith the material prepared as in Example 180.

EXAMPLE 322 (4-Benzyl-3-n-butylamino-5 -sulfamylbenzyl)dimethylamine

A mixture of (3-amino-4-benzyl-5-sulfamylbenzyl)dimethylaminedihydrochloride hemihydrate (4.0 g; dried in vacuo at 78° C. for 16hours; prepared as described in Example 209), n-butyl iodide (1.9 g),sodium hydrogen carbonate (5.0 g) and hexamethylphosphoric triamide (20ml) is stirred at 22°-25° C. for 24 hours, and is then diluted withwater (200 ml) to precipitate crude(4-benzyl-3-n-butylamino-5-sulfamylbenzyl)dimethylamine. Afterfiltration and recrystallization from ethanol it is obtained with amelting point of 111°-113° C. The material (IR, analysis) is identicalwith the material prepared as in Example 172.

EXAMPLE 323 (4-Benzyl-3-benzylamino-5-sulfamylbenzyl)dimethylamine

By replacing in Example 322 n-butyl iodide with an equimolar amount ofbenzyl bromide and following the procedure described,(4-benzyl-3-benzylamino-5-sulfamylbenzyl)dimethylamine is obtained witha melting point of 79°-80° C. The material (IR, analysis) is identicalwith the material prepared as in Example 176.

EXAMPLE 324 (3-Benzylamino-4-phenoxy-5-sulfamylbenzyl)allylamine

A solution of (3-amino-4-phenoxy-5-sulfamylbenzyl)allylamine hydrate(3.3 g; prepared as described in Example 111) and benzaldehyde (1.2 g)in methanol (35 ml) is refluxed for 16 hours. Sodium borohydride (1.0 g)is then during 30 minutes added in portions while stirring at 0°-5° C.After additional stirring for 2 hours, acetic acid (1.0 ml) followed bywater (120 ml) is cautiously added to precipitate crude(3-benzylamino-4-phenoxy-5-sulfamylbenzyl)allylamine. After filtrationand recrystallization twice from aqueous ethanol, it is obtained with amelting point of 139°-140° C. The material (IR, analysis) is identicalwith the material prepared as in Example 150.

EXAMPLES 325-330

By following the procedure described in Example 324 but using asstarting materials equimolar amounts of the appropriate 3-amino-4-R₁-5-sulfamyl N-substituted benzylamine and aldehyde as defined in TableXII below, the corresponding 4-R₁ -3-R₂ -5-sulfamyl N-substitutedbenzylamines of Table XII are obtained.

                                      Table XII                                   __________________________________________________________________________         Example in                                                                    which the                                                                     benzylamine                                                                   used is                                                                              Aldehyde used                                                     Ex. No.                                                                            described                                                                            in the reaction                                                                       Reaction product                                                                             Mp °C.                              __________________________________________________________________________    325  111    furfural                                                                              (3-(2'-furfurylamino)-4-                                                                     200-202                                                        phenoxy-5-sulfamylbenzyl)-                                                                   (see                                                           allylamine acetate                                                                           below)                                     326  111    2-thenaldehyde                                                                        (4-phenoxy-5-sulfamyl-3-(2'-                                                  thenylamino)benzyl)allylamine                                                 hemihydrate     81-83                                     327  111    3-thenaldehyde                                                                        (4-phenoxy-5-sulfamyl-3-(3'-                                                  thenylamino)benzyl)allyl-                                                     amine hydrate   85-87                                     328  110    benzaldehyde                                                                          (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)-n-butylamine                                                                 138-140                                    329  209    benzaldehyde                                                                          (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)dimethylamine                                                                  79-80                                                         hydrate                                                   330  170    benzaldehyde                                                                          (4-benzyl-3-benzylamino-5-                                                    sulfamylbenzyl)benzylamine                                                                   140-141                                    __________________________________________________________________________

The materials prepared as in Examples 325, 326, 328, 329 and 330 areidentical (IR, analysis) with the materials prepared as in Examples 259,263, 178, 176 and 179 respectively. The compound of Example 325 isisolated as the acetate.

EXAMPLE 331 (4-Benzyl-3-n-butylamino-5-sulfamylbenzyl)dimethylamine

To a vigorously stirred mixture of(3-amino-4-benzyl-5-sulfamylbenzyl)dimethylamine dihydrochloridehemihydrate (4.0 g; prepared as described in Example 209), 2 N sodiumhydroxide (60 ml) and methylene chloride (40 ml) a solution of n-butyrylchloride (1.1 g) in methylene chloride (12 ml) is dropwise added during30 minutes keeping the temperature at 0°-5° C. by external cooling.After additional stirring at 22°-25° C. for 2 hours, the organic layeris separated, washed with water and dried in the presence of magnesiumsulphate. The methylene chloride is then removed in vacuo to yield crude(4-benzyl-3-n-butyrylamido-5-sulfamylbenzyl)dimethylamine as an oil. Thecrude amine is dissolved in dry 1,2-dimethoxyethane (50 ml) and theresulting solution is dropwise added at 100° C. during 45 minutes to astirred mixture of lithium aluminium hydride (2.0 g) and1,2-dimethoxyethane (40 ml). After additional refluxing and stirring for16 hours, the mixture is cooled, and ethyl acetate (4 ml) followed bywater (8 ml) are very cautiously added. The mixture is stirred for afurther 30 minutes and is then heated on a steam-bath and filtered hot.The filtercake is carefully washed with hot 1,2-dimethoxyethane (3portions of 25 ml), whereafter the combined filtrates are evaporated invacuo to yield crude(4-benzyl-3-n-butylamino-5-sulfamylbenzyl)dimethylamine. Afterrecrystallization from ethanol it is obtained with a melting point of111°-113° C. The material (IR, analysis) is identical with the materialprepared as in Example 172.

EXAMPLE 332 (4-Benzyl-3-benzylamino-5-sulfamylbenzyl)dimethylamine

By replacing in Example 331 n-butyryl chloride with an equimolar amountof benzoyl chloride and following the procedure described,(4-benzyl-3-benzylamino-5-sulfamylbenzyl)dimethylamine is obtained as ahydrate with a melting point of 78°-80° C. The material (IR, analysis)is identical with the material prepared as in Example 176.

What we claim is:
 1. A compound of the formula I ##STR11## in which R₁ stands for an unsubstituted or substituted phenoxy, phenylthio, benzyl, phenylsulfinyl, or anilino radical;R₂ stands for a --YR₂ ' radical, in which Y represents --O--, --S--, or --NH--, and R₂ ', which may be unsubstituted or substituted, represents C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl or -alkynyl; or methyl or ethyl substituted with phenyl, furyl, thienyl or pyridyl; R₃ and R₄ which can be the same or different, and unsubstituted or substituted; stand for hydrogen or for a straight or branched C₁ -C₈ -alkyl, C₂ -C₈ - alkenyl or -alkynyl radical, a C₅ -C₇ -cycloalkyl, a phenyl, or a 5-, 6- or 7-membered heterocyclic ring system containing not more than two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, or for a C₁ -C₃ alkyl radical substituted with phenyl or with a 5-, 6- or 7-membered heterocyclic ring system containing not more than two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen; and R₄ furthermore stands for a lower carbalkoxy radical, a C₁ -C₆ alkanoyl radical, or a benzoyl radical; and salts thereof with pharmaceutically acceptable acids provided further that at least one of R₂ ', R₃ or R₄ contains a heterocyclic moiety as defined above.
 2. A compound of claim 1, in which the substituents of R₁, R₂ ', R₃, and R₄ are selected from the group consisting of halogen atoms, lower alkyl, halo-lower alkyl, nitro and amino groups, mono- or dialkylamino or acylamino groups, hydroxy groups, which may be etherified or esterified with lower aliphatic carboxylic acids, and etherified mercapto groups.
 3. A salt of a compound of formula I of claim 1 with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric and hydrobromic acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid.
 4. A compound of formula I of claim 1 in which R₁ stands for an unsubstituted or substituted phenoxy or phenylthio radical; Y stands for --NH--; and R₂ ', R₃ and R₄ have the meanings defined in claim
 1. 5. A compound of formula I of claim 1 in which R₁ stands for an unsubstituted or substituted phenoxy or phenylthio radical; Y stands for --S--; and R₂ ', R₃ and R₄ have the meanings defined in claim
 1. 6. A compound of formula I of claim 1 in which R₁ stands for an unsubstituted or substituted aniline radical; Y stands for --NH--; and R₂ ', R₃ and R₄ have the meanings defined in claim
 1. 7. A compound of formula I of claim 1 in which R₁ stands for an unsubstituted or substituted benzyl radical; Y stands for --NH--; and R₂ ', R₃ and R₄ have the meanings defined in claim
 1. 8. A compound of formula I of claim 1 in which R₁ stands for an unsubstituted or substituted benzyl radical; Y stands for --O-- or --S--; and R₂ ', R₃ and R₄ have the meanings defined in claim
 1. 9. A compound of formula I of claim 1 in which R₃ or R₄ are selected from the group consisting of furyl, thienyl, pyrrolidyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, thiazolyl, pyridyl, piperidyl, tetrahydropyridazinyl, hexahydropyridazinyl, pyrimidyl, pyrazinyl, morpholinyl, thiazinyl, perhydroazepinyl, and hexahydrooxepinyl.
 10. A compound of formula I of claim 1, in which R₂ ' when representing an alkenyl or alkynyl radical, stands for a radical with three to five carbon atoms.
 11. (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-2-picolylamine.
 12. (4-phenoxy-5-sulfamyl-3-(2'-thenylamino)benzyl)benzylamine.
 13. A pharmaceutical preparation in dosage unit form for the enteral or parenteral treatment of patients suffering from hypertension or oedemas, which comprises as an active ingredient a compound of formula I, or a salt thereof according to claim 1 with a pharmaceutically acceptable acid, and an atoxic pharmaceutically acceptable carrier, the quantity of the said active compound being between 0.1 and 50 mg.
 14. A preparation as claimed in claim 13 wherein the dosage unit contains from 0.25 to 25 mg of a compound of formula I or a salt thereof with a pharmaceutically acceptable inorganic or organic acid.
 15. A preparation as claimed in claim 13 wherein the dosage unit is in the form of a tablet.
 16. A preparation as claimed in claim 13 wherein the dosage unit is in the form of a capsule.
 17. An injectable pharmaceutical preparation in dosage unit form, containing from 0.1 mg to 50 mg of a compound of formula I of claim 1 or a salt thereof with a pharmaceutically acceptable acid, dissolved in an aqueous medium.
 18. A preparation according to claim 17, dissolved or suspended in a non-toxic, pharmaceutically acceptable vehicle.
 19. A pharmaceutical preparation for oral treatment in form of a sustained-release preparation in dosage unit form of a compound of claim 1, in which the dose of the active compound is between 0.1 to 50 mg.
 20. A preparation as claimed in claim 13 in which the dosage unit additionally contains other hypotensors, β-adrenergic receptor blocking drugs, potassiumsparing diuretics, and/or aldosterone antagonists.
 21. A preparation as claimed in claim 13 in which the dosage unit additionally contains propranolol, timolol, Rauwolfia alkaloids, Veratrum alkaloids, hydralazine, thiazide type diuretics, methyldopa, or triamterene or other potassium-sparing diuretics.
 22. A method of treating patients suffering from oedematous conditions and from hypertension, comprising administering to adult patients from 0.25 to 100 mg per day of a compound of formula I of claim 1 or an equivalent amount of a salt thereof as defined in claim
 1. 